Neuromyelitis optica (NMO) is an inflammatory disease affecting the optic nerve and spinal cord, in which autoantibodies against aquaporin 4 (AQP4) water channel protein probably play a pathogenic role. Here we show that a B-cell subpopulation, exhibiting the CD19 int CD27 high CD38 high CD180 − phenotype, is selectively increased in the peripheral blood of NMO patients and that anti-AQP4 antibodies (AQP4-Abs) are mainly produced by these cells in the blood of these patients. These B cells showed the morphological as well as the phenotypical characteristics of plasmablasts (PB) and were further expanded during NMO relapse. We also demonstrate that interleukin 6 (IL-6), shown to be increased in NMO, enhanced the survival of PB as well as their AQP4-Ab secretion, whereas the blockade of IL-6 receptor (IL-6R) signaling by anti-IL-6R antibody reduced the survival of PB in vitro. These results indicate that the IL-6-dependent B-cell subpopulation is involved in the pathogenesis of NMO, thereby providing a therapeutic strategy for targeting IL-6R signaling.neuroinflamatory disease | autoimmunity | multiple sclerosis | central nervous system | IL-6 receptor blockade N euromyelitis optica (NMO) is an inflammatory demyelinating disorder characterized by recurrent attacks of severe optic neuritis and myelitis. Unlike the conventional form of multiple sclerosis (CMS), the lesions of NMO tend to spare the cerebral white matter, especially during the early stage (1), and even a single episode of attack can cause serious neurological deficits such as total blindness and paraplegia. Accordingly, accumulation of irreversible damage to the central nervous system (CNS) along with rapid progression of disability is more frequently found in NMO compared with CMS (2).NMO can be distinguished from CMS by clinical, neuroimaging, and serological criteria (3). It is now known that serum anti-aquaporin 4 (AQP4) autoantibodies can be used as a disease marker of NMO (1, 2). AQP4 is the most abundantly expressed water channel protein in the CNS and is highly expressed in the perimicrovessel astrocyte foot processes, glia limitans, and ependyma (4). Emerging clinical and pathological observations suggest that anti-AQP4 antibodies (AQP4-Abs) play a key role in the pathogenesis of NMO. Prior studies have documented a significant correlation of serum AQP4-Ab levels with the therapeutic efficacy of plasma exchange during clinical exacerbations of NMO (2, 5). In the CNS lesions of NMO, reduced expression of AQP4 on astrocytes is evident even during the early stage (6), which is followed by the occurrence of vasculocentric destruction of astrocytes associated with perivascular deposition of complement and IgG (7).On the other hand, recent studies have suggested that AQP4-Abs alone are incapable of causing the clinical and pathological features of NMO. In fact, Hinson et al. emphasized the role of cellular immunity in combination with AQP4-Abs by showing that the attack severity of NMO was not correlated with serum AQP4-Ab levels (8). It was also d...
Objective:To evaluate the safety and efficacy of a humanized anti–interleukin-6 receptor antibody, tocilizumab (TCZ), in patients with neuromyelitis optica (NMO).Methods:Seven patients with anti–aquaporin-4 antibody (AQP4-Ab)-positive NMO or NMO spectrum disorders were recruited on the basis of their limited responsiveness to their current treatment. They were given a monthly injection of TCZ (8 mg/kg) with their current therapy for a year. We evaluated the annualized relapse rate, the Expanded Disability Status Scale score, and numerical rating scales for neurogenic pain and fatigue. Serum levels of anti-AQP4-Ab were measured with AQP4-transfected cells.Results:Six females and one male with NMO were enrolled. After a year of TCZ treatment, the annualized relapse rate decreased from 2.9 ± 1.1 to 0.4 ± 0.8 (p < 0.005). The Expanded Disability Status Scale score, neuropathic pain, and general fatigue also declined significantly. The ameliorating effects on intractable pain exceeded expectations.Conclusion:Interleukin-6 receptor blockade is a promising therapeutic option for NMO.Classification of evidence:This study provides Class IV evidence that in patients with NMO, TCZ reduces relapse rate, neuropathic pain, and fatigue.
Multiple sclerosis (MS) is a CD4+ T cell-mediated autoimmune disease affecting the central nervous system. It was largely accepted that Th1 cells driven by IL-12 were pathogenic T cells in human MS and experimental autoimmune encephalomyelitis, an animal model of MS. Recent data have established that IL-17-producing CD4+ T cells, driven by IL-23 and referred to as Th17 cells, play a pivotal role in the pathogenesis of EAE. A combination of TGF-beta and IL-6 induce Th17 cell lineage commitment via expression of transcription factor RORgammat. Th17 cells and induced Foxp3+ T regulatory cells are in reciprocal position in the T cell lineage commitment governed by TGF-beta and IL-6. The vitamin A metabolite retinoic acid is involved in this process via TGF-beta dependent induction of Foxp3. We have demonstrated that human Th17 cells could be identified as CCR2+ CCR5- memory CD4+ T cells. It is becoming clear that IL-23/Th17 axis also plays an important role in the pathogenesis of various human autoimmune diseases including MS. Additionally, accumulating evidences raise a possibility that CCR2 on Th17 cells may be a therapeutic target in MS.
Multiple sclerosis is a chronic demyelinating disease of presumed autoimmune pathogenesis. The patients with multiple sclerosis typically shows alternating relapse and remission in the early stage of illness. We previously found that in the majority of multiple sclerosis patients in a state of remission, natural killer (NK) cells contain unusually high frequencies of the cells expressing CD95 (Fas) on their surface (>36.0%). Here we report that in such 'CD95+ NK-high' patients, NK cells may actively suppress potentially pathogenic autoimmune T cells that can mediate the inflammatory responses in the CNS. Using peripheral blood mononuclear cells (PBMCs) derived from 'CD95+ NK-high' or 'CD95+ NK-low' multiple sclerosis in a state of remission, we studied the effect of NK cell depletion on the memory T cell response to myelin basic protein (MBP), a major target antigen of multiple sclerosis. When we stimulated PBMCs of the 'CD95+ NK-high' multiple sclerosis after depleting CD56+ NK cells, a significant proportion of CD4+ T cells (1/2000 to 1/200) responded rapidly to MBP by secreting interferon (IFN)-gamma, whereas such a rapid T cell response to MBP could not be detected in the presence of NK cells. Nor did we detect the memory response to MBP in the 'CD95+ NK-low' multiple sclerosis patients in remission or healthy subjects, regardless of whether NK cells were depleted or not. Depletion of cells expressing CD16, another NK cell marker, also caused IFN-gamma secretion from MBP-reactive CD4+ T cells in the PBMCs from 'CD95+ NK-high' multiple sclerosis. Moreover, we showed that NK cells from 'CD95+ NK-high' multiple sclerosis could inhibit the antigen-driven secretion of IFN-gamma by autologous MBP-specific T cell clones in vitro. These results indicate that NK cells may regulate activation of autoimmune memory T cells in an antigen non-specific fashion to maintain the clinical remission in 'CD95(+) NK-high' multiple sclerosis patients.
Recent reports have shown that IL-17-producing CD4+ T cells (Th17 cells) belong to a distinct helper T cell lineage and are critically involved in the pathogenesis of autoimmune diseases and allergies. However, the chemokine receptor profile of Th17 cells remains to be clarified. In this study, we report that human Th17 cells are identified as CCR2+CCR5− memory CD4+ T cells. Analysis of PBMC from healthy donors showed that CCR2+ cells produce much larger amounts of IL-17 than CCR2− cells, indicating the preferential expression of CCR2 on Th17 cells. Notably, CCR2+CCR5− memory CD4+ T cells produced a large amount of IL-17 and little IFN-γ, whereas CCR2+CCR5+ cells reciprocally produced an enormous amount of IFN-γ but little IL-17. Moreover, a higher expression of T-bet was seen in the CCR5+ memory T cells. These results indicate that absence of CCR5 distinguishes human Th17 cells from Th1 cells.
Neuromyelitis optica (NMO) is a disabling autoimmune disease associated with an elevation of anti-aquaporin 4 (AQP4) autoantibodies. Here, we present a case with NMO who responded to monthly administration of the anti-IL-6 receptor antibody tocilizumab. The treatment rapidly reduced the elevated numbers of plasmablasts and anti-AQP4 autoantibodies in the patient. Furthermore, neuropathic pain and disability scores gradually improved. Tocilizumab may be considered as a therapeutic option for NMO.
Multiple sclerosis (MS) is a demyelinating disease of the CNS that is presumably mediated by CD4+ autoimmune T cells. Although both Th1 and Th17 cells have the potential to cause inflammatory CNS pathology in rodents, the identity of pathogenic T cells remains unclear in human MS. Given that each Th cell subset preferentially expresses specific chemokine receptors, we were interested to know whether T cells defined by a particular chemokine receptor profile play an active role in the pathogenesis of MS. In this article, we report that CCR2+CCR5+ T cells constitute a unique population selectively enriched in the cerebrospinal fluid of MS patients during relapse but not in patients with other neurologic diseases. After polyclonal stimulation, the CCR2+CCR5+ T cells exhibited a distinct ability to produce matrix metalloproteinase-9 and osteopontin, which are involved in the CNS pathology of MS. Furthermore, after TCR stimulation, the CCR2+CCR5+ T cells showed a higher invasive potential across an in vitro blood–brain barrier model compared with other T cells. Of note, the CCR2+CCR5+ T cells from MS patients in relapse are reactive to myelin basic protein, as assessed by production of IFN-γ. We also demonstrated that the CCR6−, but not the CCR6+, population within CCR2+CCR5+ T cells was highly enriched in the cerebrospinal fluid during MS relapse (p < 0.0005) and expressed higher levels of IFN-γ and matrix metalloproteinase-9. Taken together, we propose that autoimmune CCR2+CCR5+CCR6− Th1 cells play a crucial role in the pathogenesis of MS.
Neuromyelitis optica (NMO) is an inflammatory disease characterized by recurrent attacks of optic neuritis and myelitis. It is generally accepted that autoantibodies against aquaporin 4 water channel protein play a pathogenic role in neuromyelitis optica. We have recently reported that plasmablasts are increased in the peripheral blood of this autoimmune disease, and are capable of producing autoantibodies against aquaporin 4. Here, we demonstrate that CD138+HLA-DR+ plasmablasts, a subset of IgG-producing cells, are increased in the peripheral blood and are enriched among the cerebrospinal fluid (CSF) lymphocytes during the relapse of neuromyelitis optica. Notably, these CD138+HLA-DR+ plasmablasts overexpress CXCR3, whose ligands are present in the cerebrospinal fluid during the relapse of neuromyelitis optica. These results led us to speculate that plasmablasts producing anti-aquaporin 4 autoantibodies might traffic toward the central nervous system (CNS). Furthermore, we performed single-cell sorting of plasmablasts from peripheral blood and CSF samples from NMO and sequenced the complementarity-determining regions (CDRs) of the IgG heavy chain expressed by the sorted plasmablast clones. There were high frequencies of mutations in the CDRs compared with framework regions, indicating that these plasmablast clones would represent a post-germinal center B-cell lineage. Consistent with the preceding results, the plasmablast clones from the peripheral blood shared the same CDR sequences with the clones from the CSF. These results indicate that IgG-producing plasmablasts, which are guided by helper T-cells, may migrate from the peripheral blood preferentially to the CSF. Since migratory plasmablasts could be involved in the inflammatory pathology of NMO, the B-cell subset and their migration might be an attractive therapeutic target.
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