Abstract
BackgroundNeuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system (CNS), which is characterized by the presence of pathogenic serum autoantibodies against aquaporin 4 (AQP4) in the vast majority of patients. The contribution of T cells to the formation of astrocyte destructive lesions is currently unclear. However, active human NMO lesions contain CD4+ T-lymphocytes expressing the activation marker Ox40, and the expression is more profound compared to that seen in MS lesions of comparable activity. Therefore, we analyzed the role of T-cell activation within the CNS in the initiation of NMO lesions in an experimental model of co-transfer of different encephalitogenic T-cells and human AQP4 antibody containing NMO immunoglobulin (NMO IgG). We further studied the expression of the T-cell activation marker Ox40 in NMO and multiple sclerosis lesions in different stages of activity.ResultsAll encephalitogenic T-cell lines used in our experiments induced brain inflammation with a comparable extent of blood brain barrier damage, allowing human NMO IgG to penetrate into the brain and spinal cord tissue. However, astrocyte destructive NMO lesions were only seen with T-cells, which showed signs of activation in the lesions. T-cell activation was reflected by the expression of the activation marker Ox40 and pronounced production of γ-IFN, which was able to increase the production of complement proteins and of the Fc gamma III receptor (Fcgr3) and decreased production of complement inhibitory protein Factor H in microglia.ConclusionsOur data indicate that local activation of T-cells provide an inflammatory environment in the CNS, which allows AQP4 auto-antibodies to induce astrocyte destructive NMO-like lesions.
Highlights
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system (CNS), which is characterized by the presence of pathogenic serum autoantibodies against aquaporin 4 (AQP4) in the vast majority of patients
Active NMO lesions contain activated CD4+ T cells CD4+ T cells expressing the activation markers OX40 and proliferating cell nuclear antigen (PCNA) are found in NMO lesions, independent of their location within the neuraxis (Figures 1 and 2)
T cells with different CNS antigen-specificities are differentially activated within the CNS To address this question, we studied the extent of T cell activation in EAE provoked by T cells with different CNS antigen-specificities
Summary
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system (CNS), which is characterized by the presence of pathogenic serum autoantibodies against aquaporin 4 (AQP4) in the vast majority of patients. Neuromyelitis optica (NMO) is an astrocytopathic disease of the central nervous system (CNS) characterized by optic neuritis, transverse myelitis, and – in the vast majority of patients – by the presence of specific autoantibodies, the so-called NMO-IgGs [1]. These antibodies are directed against aquaporin 4 (AQP4), a water channel enriched on astrocytic processes at the glia limitans [2,3], and they are pathogenic. Since the antigen recognition of T cells found in NMO lesions is still unknown, the findings in experimental NMO raise important questions: Are all CNS antigen-specific T cells able to initiate astrocyte-destructive lesions in NMO-IgG seropositive hosts? And if not, what are the requirements for T cells to do so? These questions were answered in the current study
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