Immunological Aspects of Approved MS Therapeutics

Rommer, Paulus; Milo, Ron; Han, May; Satyanarayan, Sammita; Sellner, Johann; Hauer, Larissa; Illés, Zsolt; Warnke, Clemens; Laurent, Sarah; Weber, Martin; Zhang, Yinan; Stüve, Olaf

doi:10.3389/fimmu.2019.01564

Cited by 123 publications

(108 citation statements)

References 277 publications

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“…Multiple sclerosis (MS) is a complex, highly debilitating inflammatory disease of the central nervous system (CNS) and represents the most common cause of neurological disability in young adults (1). Most of the available drugs display efficacy in the relapsing-remitting (RR-MS) form of the disease (2), where frequent waves of infiltrating immune cells into the CNS lead to demyelination, but not in progressive MS, where oligodendrocyte and neuroaxonal damage is sustained by compartmentalized inflammation due to glial dysregulation (3). After several years of disease most of the RR-MS patients enter the progressive stage (called secondary progressive MS, SP-MS), characterized by steady accumulation of disability in absence of acute clinical events (4).…”

Section: Introductionmentioning

confidence: 99%

Siponimod (BAF312) Activates Nrf2 While Hampering NFκB in Human Astrocytes, and Protects From Astrocyte-Induced Neurodegeneration

Colombo¹,

Bassani²,

Angelis³

et al. 2020

Front. Immunol.

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Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system (CNS) with heterogeneous pathophysiology. In its progressive course oligodendrocyte and neuroaxonal damage is sustained by compartmentalized inflammation due to glial dysregulation. Siponimod (BAF312), a modulator of two sphingosine-1-phosphate (S1P) receptors (S1P1 and S1P5) is the first oral treatment specifically approved for active secondary progressive MS. To address potential direct effects of BAF312 on glial function and glia-neuron interaction, we set up a series of in vitro functional assays with astrocytes generated from human fibroblasts. These cells displayed the typical morphology and markers of astroglia, and were susceptible to the action of inflammatory mediators and BAF312, because expressing receptors for IL1, IL17, and S1P (namely S1P1 and S1P3). Targeting of S1P signaling by BAF312 inhibited NFκB translocation evoked by inflammatory cytokines, indicating a direct anti-inflammatory activity of the drug on the human astrocyte. Further, while glia cells exposed to IL1 or IL17 downregulated protein expression of glutamate transporters, BAF312-treated astrocytes maintained high levels of GLAST and GLT1 regardless of the presence of inflammatory mediators. Interestingly, despite potential glial susceptibility to S1P signaling via S1P3, which is not targeted by BAF312, NFκB translocation and downregulation of glutamate transporters in response to S1P were inhibited at similar levels by BAF312 and FTY720, another S1P signaling modulator targeting also S1P3. Accordingly, specific inhibition of S1P1 via NIBR-0213 blocked S1P-evoked NFκB translocation, demonstrating that modulation of S1P1 is sufficient to dampen signaling via other S1P receptors. Considering that NFκB-dependent responses are regulated by Nrf2, we measured activation of this critical transcription factor for anti-oxidant reactions, and observed that BAF312 rapidly induced nuclear translocation of Nrf2, but this effect was attenuated in the presence of an inflammatory milieu. Finally, in vitro experiments with spinal neurons exposed to astrocyte-conditioned media showed that modulation of

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Section: Introductionmentioning

confidence: 99%

Siponimod (BAF312) Activates Nrf2 While Hampering NFκB in Human Astrocytes, and Protects From Astrocyte-Induced Neurodegeneration

Colombo¹,

Bassani²,

Angelis³

et al. 2020

Front. Immunol.

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“…IFN-β plays an important role in activating immune cells and suppressing virus replication (26)(27)(28)(29)(30)(31), and ZIKV infection leads to low levels of type I IFNs (32). Here, we initially showed that IFN-β mRNA was significantly induced by poly(I:C), but such induction was suppressed by ZIKV infection (Figure 1A).…”

Section: Zikv Ns5 Represses Ifn-β Production By Targeting the Rig-i Pmentioning

confidence: 84%

NS5 Conservative Site Is Required for Zika Virus to Restrict the RIG-I Signaling

Wang

et al. 2020

Front. Immunol.

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During host-virus co-evolution, cells develop innate immune systems to inhibit virus invasion, while viruses employ strategies to suppress immune responses and maintain infection. Here, we reveal that Zika virus (ZIKV), a re-emerging arbovirus causing public concerns and devastating complications, restricts host immune responses through a distinct mechanism. ZIKV nonstructural protein 5 (NS5) interacts with the host retinoic acid-inducible gene I (RIG-I), an essential signaling molecule for defending pathogen infections. NS5 subsequently represses K63-linked polyubiquitination of RIG-I, attenuates the phosphorylation and nuclear translocation of interferon regulatory factor 3 (IRF3), and inhibits the expression and production of interferon-β (IFN-β), thereby restricting the RIG-I signaling pathway. Interestingly, we demonstrate that the methyltransferase (MTase) domain of NS5 is required for the repression of RIG-I ubiquitination, IRF3 activation, and IFN-β production. Detailed studies further reveal that the conservative active site D146 of NS5 is critical for the suppression of the RIG-I signaling. Therefore, we uncover an essential role of NS5 conservative site D146 in ZIKV-mediated repression of innate immune system, illustrate a distinct mechanism by which ZIKV evades host immune responses, and discover a potential target for anti-viral infection.

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“…Persistent lymphopenia or marked drop of lymphocytes is a known risk factor for opportunistic CNS infection [32]. Of note, HSE has been reported not only after immunosuppressive therapy but also in multiple sclerosis (MS) by lymphocyte-lowering immunotherapies or interference with the migratory action of lymphocytes [10,33,34]. Neutrophils have an essential biological function for both innate and adaptive immune responses.…”

Section: Discussionmentioning

confidence: 99%

Cerebral HSV-1 Vasculitis as a Fatal Complication of Immunosuppression in Non-Hodgkin´s Lymphoma: A Case Report and Review of the Literature

Nardone

Carnicelli²,

Brigo³

et al. 2020

Pathogens

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Patients with lymphoma are predisposed to infection because of the immunocompromised state related to the disease itself and as a consequence of chemo-/radiotherapy. Here, we report a case of Herpes-simplex virus encephalitis (HSE) in an immunosuppressed patient with splenic marginal zone lymphoma (SMZL), a rare indolent variant of non-Hodgkin´s lymphoma (NHL). The course was complicated febrile neutropenia and HSV-1-related cerebral vasculitis causing progressive ischemic stroke. This case illustrates the expanding spectrum of atypical clinical and radiological manifestations of HSE in patients treated with myelotoxic drugs. Moreover, we summarize the few central nervous system manifestations of SMZL reported in the literature and discuss distinct causes of neurological deterioration in patients with NHL.

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Immunological Aspects of Approved MS Therapeutics

Cited by 123 publications

References 277 publications

Siponimod (BAF312) Activates Nrf2 While Hampering NFκB in Human Astrocytes, and Protects From Astrocyte-Induced Neurodegeneration

Siponimod (BAF312) Activates Nrf2 While Hampering NFκB in Human Astrocytes, and Protects From Astrocyte-Induced Neurodegeneration

NS5 Conservative Site Is Required for Zika Virus to Restrict the RIG-I Signaling

Cerebral HSV-1 Vasculitis as a Fatal Complication of Immunosuppression in Non-Hodgkin´s Lymphoma: A Case Report and Review of the Literature

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