Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica

Abstract

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...

CNS Aquaporin‐4‐specific B cells connect with multiple B‐cell compartments in neuromyelitis optica spectrum disorder

“…We used Ig transcriptome and Ig proteome analyses to evaluate the clonal relationship between different peripheral B‐cell populations and AQP4‐specific B cells in the CSF of active seropositive NMO patients. In contrast to prior studies,16, 17 we identified clonal relationships between CSF B cells and circulating class‐switched memory, DN memory, and plasmablast populations. We also observed an overlap between CSF B cells and memory B cells and plasmablasts from the spleen of one patient.…”

“…Interestingly, a high degree of connectivity was observed between ASCs and activated naïve B cells in active systemic lupus erythematosus patients 12. Our data suggest that naïve B cells may also be actively recruited into the enhanced ASC response associated with NMOSD clinical relapse 16. As circulating IgG is the product of long‐lived bone marrow‐resident plasma cells, these newly emerging AQP4‐specific B‐cell clones likely contribute little to the serum AQP4‐IgG that passively crosses the blood–brain barrier during relapse.…”

“…Previous studies have documented elevated circulating plasmablasts in NMOSD patients 16, 17. Due to the close linear relationship between clonal populations of circul ating peripheral blood DN B cells and AQP4‐reactive CSF plasmablasts, we examined the fraction of DN B cells in the peripheral blood of 11 NMOSD patients (seven in this study), 15 multiple sclerosis (MS) patients, and 15 healthy controls by FACS (Fig.…”

N‐methyl‐D‐aspartate receptor antibody production from germinal center reactions: Therapeutic implications

“…The NR1‐IgG were unlikely to have arisen from pre‐existing circulating ASCs derived ex vivo, given that they were not generated under conditions known to maintain ASCs in culture (IL‐6 ± BAFF) 16. By contrast, under conditions known to proliferate circulating B cells (including IL‐2 and R848),10 NR1‐IgG was consistently detected in culture supernatants both with and without CD40‐ligand (Fig 3).…”

Interleukin-6 Blockade as Rescue Therapy in Autoimmune Encephalitis

“…Recently, tocilizumab has been used to treat neuromyelitis optica (NMO) [9], an autoimmune CNS disease with pathogenic antiaquaporin-4 autoantibodies, although the immunopathogenesis of NMO is complex with pathological evidence of autoantibody, complement, T cells, B cells, neutrophils, and eosinophils [10]. IL-6 is elevated in NMO attacks, is involved in autoantibody production, and is used as a disease biomarker [11]. By contrast, the literature regarding IL-6 in AE is small and only now emerging, although some small studies have shown that IL-6 is elevated in AE [12,13].…”