Enhanced IL-6 Production in Aquaporin-4 Antibody Positive Neuromyelitis Optica Patients

İçöz, Sema; Tüzün, Erdem; Kürtüncü, Murat; Durmuş, Hacer; Mutlu, Melike; Eraksoy, Mefküre; Akman‐Demir, Gülşen

doi:10.3109/00207450903428970

Cited by 98 publications

(46 citation statements)

References 9 publications

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“…Our further demonstration that astrocytes exposed to NMO-F(ab′) 2 release IL-6, without internalizing AQP4, is consistent with the documented proinflammatory response stimulated in astrocytes as an outcome of AQP4 clustering: secretion of complement components, chemokines, and cytokines (13,14). IL-6 is a critical mediator of CNS inflammation in NMO (23,24), as evidenced by the therapeutic benefit of monoclonal IgG blockade of IL-6 (25). Ex vivo, IL-6 released by astrocytes exposed to NMO-IgG reduced CNS capillary endothelial barrier function, increased CCL2 and CXCL8 production, and promoted leukocyte transmigration under flow conditions; these effects were neutralized by IL-6-specific IgG (12).…”

Section: Discussionsupporting

confidence: 59%

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor

Hinson

Clift

Luo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Aquaporin-4 (AQP4) water channel-specific IgG distinguishes neuromyelitis optica (NMO) from multiple sclerosis and causes characteristic immunopathology in which central nervous system (CNS) demyelination is secondary. Early events initiating the pathophysiological outcomes of IgG binding to astrocytic AQP4 are poorly understood. CNS lesions reflect events documented in vitro following IgG interaction with AQP4: AQP4 internalization, attenuated glutamate uptake, intramyelinic edema, interleukin-6 release, complement activation, inflammatory cell recruitment, and demyelination. Here, we demonstrate that AQP4 internalization requires AQP4-bound IgG to engage an astrocytic Fcγ receptor (FcγR). IgG-lacking Fc redistributes AQP4 within the plasma membrane and induces interleukin-6 release. However, AQP4 endocytosis requires an activating FcγR's gamma subunit and involves astrocytic membrane loss of an inhibitory FcγR, CD32B. Interaction of the IgG-AQP4 complex with FcγRs triggers coendocytosis of the excitatory amino acid transporter 2 (EAAT2). Requirement of FcγR engagement for internalization of two astrocytic membrane proteins critical to CNS homeostasis identifies a complement-independent, upstream target for potential early therapeutic intervention in NMO.N euromyelitis optica (NMO) is a relapsing inflammatory autoimmune demyelinating disease of the central nervous system (CNS), long considered a severe form of multiple sclerosis (MS). Attacks are generally more severe, onset of paralysis and blindness more rapid (1), and standard MS therapies can worsen NMO (2, 3). A specific serum IgG allows early distinction from MS, thus ensuring timely appropriate therapy (4, 5).The aquaporin-4 (AQP4) water channel is the CNS target (4). Outcomes documented in vitro after NMO-IgG binds to the AQP4 extracellular domain on astrocytes include AQP4 endocytosis and lysosomal degradation, loss of its physically linked major excitatory amino acid transporter 2 (EAAT2), reduced glutamate uptake, impaired water fluxes, granulocyte chemotaxis, and complement factor transcription, secretion, and activation (1, 6-11). Ensuing endothelial permeation of circulating immunoglobulins, complement components, and leukocytes magnifies the initial inflammatory response (6-12). Immunopathological analyses of NMO patients' CNS tissues attest to these events occurring in vivo and inform lesional evolution at the target astrocyte level (1). The blood-brain barrier (BBB) does not absolutely restrict IgG entry into the CNS, but it does exclude macromolecular C1q, essential for activating the classical complement cascade.Experimental studies of lesional events in vitro and in animal models of NMO have emphasized complement-mediated inflammation and astrocyte cytolysis, late events associated with extensive BBB disruption. A neglected potential initiator of NMO pathophysiology is the AQP4-IgG-activated astrocyte's response: synthesis and secretion of complement, cytokines, chemokines (12-14), and inflammatory mediators attracting NMO-characteristic gra...

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Section: Discussionsupporting

confidence: 59%

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor

Hinson

Clift

Luo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…It would be interesting to investigate which organs blood PB move to during the course of NMO. The levels of IL-6 in the serum and CSF are elevated in NMO compared with HS or CMS patients (27,28). In this regard, it is of note that blocking IL-6R signaling was found to dramatically reduce the survival of PB ex vivo, which was dependent on the presence of autologous serum containing IL-6.…”

Section: Discussionmentioning

confidence: 87%

“…IL-6 induces B-cell differentiation into plasma cells, maintains early plasma cell survival, and enhances plasma cell IgG secretion (24). Besides, IL-6 is elevated in the cerebrospinal fluid (CSF) or peripheral blood of NMO patients compared with that of CMS patients and HS (27,28). In a rodent autoimmunity model, IL-6 deficiency caused impaired autoantibody secretion by B cells (29).…”

Section: Expanded Cells Resemble Early Plasma Cells In Gene Expressiomentioning

confidence: 99%

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

Chihara

Aranami

Sato

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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297

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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...

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“…In addition, Th17 cells have been shown to enhance CNS inflammation by inducing the expression of inflammatory chemokines and IL-6 in astrocytes (39)(40)(41). In fact, patients with NMO, who generally have higher IL-17 and IL-6 levels in the cerebrospinal fluid than those of MS patients, tend to exhibit severe pathological changes (42)(43)(44)(45). The clinical severities in MS patients with high Sema4A levels may be partially explained by the increased permeability of the BBB and subsequent infiltration of Th17 cells into the CNS.…”

Section: Discussionmentioning

confidence: 99%

Elevation of Sema4A Implicates Th Cell Skewing and the Efficacy of IFN-β Therapy in Multiple Sclerosis

Nakatsuji

Okuno

Moriya

et al. 2012

The Journal of Immunology

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Multiple sclerosis (MS) is a demyelinating autoimmune disease of the CNS and a leading cause of lasting neurologic disabilities in young adults. Although the precise mechanism remains incompletely understood, Ag presentation and subsequent myelin-reactive CD4+ T cell activation/differentiation are essential for the pathogenesis of MS. Although semaphorins were initially identified as axon guidance cues during neural development, several semaphorins are crucially involved in various phases of immune responses. Sema4A is one of the membrane-type class IV semaphorins, which we originally identified from the cDNA library of dendritic cell (DC). Sema4A plays critical roles in T cell activation and Th1 differentiation during the course of experimental autoimmune encephalomyelitis, an animal model of MS; however, its pathological involvement in human MS has not been determined. In this study, we report that Sema4A is increased in the sera of patients with MS. The expression of Sema4A is increased on DCs in MS patients and shed from these cells in a metalloproteinase-dependent manner. DC-derived Sema4A is not only critical for Th1 but also for Th17 cell differentiation, and MS patients with high Sema4A levels exhibit Th17 skewing. Furthermore, patients with high Sema4A levels have more severe disabilities and are unresponsive to IFN-β treatment. Taken together, our results suggest that Sema4A is involved in the pathogenesis of MS by promoting Th17 skewing.

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Enhanced IL-6 Production in Aquaporin-4 Antibody Positive Neuromyelitis Optica Patients

Cited by 98 publications

References 9 publications

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor

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

Elevation of Sema4A Implicates Th Cell Skewing and the Efficacy of IFN-β Therapy in Multiple Sclerosis

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