T cell-activation in neuromyelitis optica lesions plays a role in their formation

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.

Neurodegeneration in multiple sclerosis and neuromyelitis optica

“…Inflammation: Although both diseases are associated with a chronic inflammatory reaction, the nature of the inflammatory response seems to be different 89. This is further supported by the observation that some of the anti-inflammatory treatments that are highly effective in patients with MS fail in NMO or may even amplify the disease.…”

“…The key characteristics of NMO pathology are loss of AQP4 immunoreactivity on astrocytes with vasculocentric deposition of immunoglobulins and activated complement86–88 and infiltration of inflammatory cells, including lymphocytes, plasma cells89 and granulocytes 88. These findings are similar in the definite and limited form of NMO (NMOSD) 90.…”

OX40, OX40L and Autoimmunity: a Comprehensive Review

“…Coeliac disease OX40-positive lymphocytes present in disease but not control duodenal biopsies [27]; peripheral OX40 expression not affected [152] Rheumatoid arthritis Increased OX40-positivity on lymphocytes in synovial fluid from inflamed joints [26,153,123,154,110] OX40L expression on sublining layer of sinovium from inflamed joints [123,155] Reduced sOX40 [110] Increased sOX40L with correlation with autoantibody status [110] Inflammatory myositis OX40 expression present in inflammatory myopathies but not controls [156,157] OX40L seen on T cells, B cells, macrophages and myeloid dendritic cells in inflammatory myopathies but not controls [156] Uveitis Multiple OX40-positive infiltrating lymphocytes from ciliary bodes of eyes enucleated for uveitis [139] Type 1 Diabetes Mellitus Increased proportion of CD4+ cells positive in peripheral blood of newly diagnosed paediatric cases [106] Systemic sclerosis Elevated serum sOX40 concentrations in comparison with SLE and healthy controls [109] Graves' Thyroiditis Increased OX40-positivity of circulating CD4+ T cells in patients with anti-TSHR antibodies [112,158,159] Increased OX40L-positivity of circulating CD4+ T cells in patients with anti-TSHR antibodies [112] Elevations of sOX40L [48] Multiple sclerosis Reduction in OX40+CD26+ peripheral CD4+ T cells correlating with clinical response after treatment with natalizumab [104] OX40 expressed in MS brain and cord sections [126] Neuromyelitis optica Increased OX40 positivity of pathological brain specimens [126] Sjögren syndrome Increased OX40 expression on peripheral T cells [160] Increased OX40L expression on peripheral B cells and monocytes [160] Myasthenia gravis Increased thymic OX40 staining around germinal centres [161] OX40L present in myasthenia gravis thyroid but not control [161] Increased OX40-staining on peripheral CD4+ T cells [105] Granul...…”

“…In this model, OX40 expression is increased in the draining lymph nodes of inflamed joints and expression increases before clinical signs appear [125]. In rat EAE, there was analogous early OX40 activation on antigen-specific lymphocytes before the onset of clinical signs [126].…”

Cytokine and Chemokine Profiles in Patients with Neuromyelitis Optica Spectrum Disorder

“…In the majority of NMO patients, the presence of highly specific serum antibody against aquaporin-4 (known as AQP4-IgG) helps to distinguish NMO from multiple sclerosis (MS), and expands the diagnosis to include neuromyelitis optica spectrum disorder (NMOSD). In addition to AQP4-IgG, growing evidence shows that complements, cytokines, chemokines, T cells-granulocytes, and macrophages also contribute to the complex pathogenesis of NMOSD [1,2]. …”