Jens Ingwersen

Modulation of adult hippocampal neurogenesis during myelin-directed autoimmune neuroinflammation

In chronic autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS) clinical signs of cognitive dysfunction have been associated with structural changes in the hippocampus. Moreover, experimental studies indicate that inflammatory responses within the CNS modulate the homeostasis of newborn cells in the adult dentate gyrus (DG). However, it remained open whether such changes happen regardless of the primary immunological target or whether a CNS antigen‐directed T lymphocyte‐mediated autoimmune response may exert a specific impact. We therefore induced experimental autoimmune encephalomyelitis (EAE), a common model of MS serving as a paradigm for a CNS‐specific immune response, by immunizing C57BL/6 mice with encephalitogenic myelin oligodendrocyte glycoprotein (MOG) p35‐55. In EAE animals, we found enhanced de novo generation and survival of doublecortin (DCX)‐positive immature neurons when compared with controls immunized with CNS‐irrelevant antigen (ovalbumine). However, despite activation of neurogenesis, we observed a reduced capacity of these cells to generate mature neurons. Moreover, the high number of newly born cells retained the expression of the glial marker GFAP. These effects were associated with downregulation of pro‐neurogenic factors Neurogenin1 and Neurogenin2 and dysregulation of Notch, β‐catenin, Sonic Hedgehog (Shh) signaling as suggested by altered gene expression of effector molecules. Thus, a CNS antigen‐specific immune response leads to an aberrant differentiation of neural precursors associated with dysbalance of signaling pathways relevant for adult hippocampal neurogenesis. These results may further extend our understanding of disturbed regeneration in the course of chronic inflammatory CNS diseases such as MS.

Neuromyelitis optica and pregnancy during therapeutic B cell depletion: infant exposure to anti-AQP4 antibody and prevention of rebound relapses with low-dose rituximab postpartum

Neuromyelitis optica (NMO) predominantly affects women, some in childbearing age, and requires early therapeutic intervention to prevent disabling relapses. We report an anti-AQP4 antibody-seropositive patient who became pregnant seven months after low-dose (100 mg) rituximab application. Pregnancy showed no complications, and low-dose rituximab restarted two days after delivery resulted in neurological stability for 24 months. Remarkably, her otherwise healthy newborn presented with anti-AQP4 antibody and reduced B lymphocyte counts in umbilical cord blood, which normalized three months later. Confirming and extending previous reports, our case suggests that low-dose rituximab might be compatible with pregnancy and prevent rebound NMO disease activity postpartum.

Natalizumab restores aberrant miRNA expression profile in multiple sclerosis and reveals a critical role for miR-20b.

To identify microRNAs (miRNAs) regulated by anti‐α4 integrin monoclonal antibody therapy (natalizumab) in the peripheral blood of patients with relapsing‐remitting (RR) multiple sclerosis (MS) and to confirm their role in experimental settings in vivo.

IFNβ secreted by microglia mediates clearance of myelin debris in CNS autoimmunity

IntroductionMultiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system (CNS) leading to progressive neurological disability. Interferon β (IFNβ) represents a standard treatment for relapsing-remitting MS and exogenous administration of IFNβ exhibits protective effects in experimentally induced CNS autoimmunity. Also, genetic deletion of IFNβ in mice leads to an aggravation of disease symptoms in the MS model of experimental autoimmune encephalomyelitis (EAE). However, neither the underlying mechanisms mediating the beneficial effects nor the cellular source of IFNβ have been fully elucidated.ResultsIn this report, a subpopulation of activated microglia was identified as the major producers of IFNβ in the CNS at the peak of EAE using an IFNβ-fluorescence reporter mouse model. These IFNβ expressing microglia specifically localized to active CNS lesions and were associated with myelin debris in demyelinated cerebellar organotypic slice cultures (OSCs). In response to IFNβ microglia showed an enhanced capacity to phagocytose myelin in vitro and up-regulated the expression of phagocytosis-associated genes. IFNβ treatment was further sufficient to stimulate association of microglia with myelin debris in OSCs. Moreover, IFNβ-producing microglia mediated an enhanced removal of myelin debris when co-transplanted onto demyelinated OSCs as compared to IFNβ non-producing microglia.ConclusionsThese data identify activated microglia as the major producers of protective IFNβ at the peak of EAE and as orchestrators of IFNβ-induced clearance of myelin debris.

Dual roles of the adenosine A2a receptor in autoimmune neuroinflammation

BackgroundConditions of inflammatory tissue distress are associated with high extracellular levels of adenosine, due to increased adenosine triphosphate (ATP) degradation upon cellular stress or the release of extracellular ATP upon cell death, which can be degraded to adenosine by membrane-bound ecto-enzymes like CD39 and CD73. Adenosine is recognised to mediate anti-inflammatory effects via the adenosine A2a receptor (A2aR), as shown in experimental models of arthritis. Here, using pharmacological interventions and genetic inactivation, we investigated the roles of A2aR in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).MethodsWe used two independent mouse EAE variants, i.e. active immunization in C57BL/6 with myelin oligodendrocyte glycoprotein (MOG)35-55 or transfer-EAE by proteolipid protein (PLP)139-155-stimulated T lymphocytes and EAE in mice treated with A2aR-agonist CGS21680 at different stages of disease course and in mice lacking A2aR (A2aR−/−) compared to direct wild-type littermates. In EAE, we analysed myelin-specific proliferation and cytokine synthesis ex vivo, as well as inflammation and demyelination by immunohistochemistry. In vitro, we investigated the effect of A2aR on migration of CD4+ T cells, macrophages and microglia, as well as the impact of A2aR on phagocytosis of macrophages and microglia. Statistical tests were Mann-Whitney U and Student’s t test.ResultsWe found an upregulation of A2aR in the central nervous system (CNS) in EAE, predominantly detected on T cells and macrophages/microglia within the inflamed tissue. Preventive EAE treatment with A2aR-specific agonist inhibited myelin-specific T cell proliferation ex vivo and ameliorated disease, while application of the same agonist after disease onset exacerbated non-remitting EAE progression and resulted in more severe tissue destruction. Accordingly, A2aR-deficient mice showed accelerated and exacerbated disease manifestation with increased frequencies of IFN-γ-, IL-17- and GM-CSF-producing CD4+ T helper cells and higher numbers of inflammatory lesions in the early stage. However, EAE quickly ameliorated and myelin debris accumulation was lower in A2aR−/− mice. In vitro, activation of A2aR inhibited phagocytosis of myelin by macrophages and primary microglia as well as migration of CD4+ T cells, macrophages and primary microglia.ConclusionsA2aR activation exerts a complex pattern in chronic autoimmune neurodegeneration: while providing anti-inflammatory effects on T cells and thus protection at early stages, A2aR seems to play a detrimental role during later stages of disease and may thus contribute to sustained tissue damage within the inflamed CNS.

Advances in and Algorithms for the Treatment of Relapsing-Remitting Multiple Sclerosis.

Treatment options in relapsing-remitting multiple sclerosis have increased considerably in recent years; currently, a dozen different preparations of disease-modifying therapies are available and some more are expected to be marketed soon. For the treating neurologist this broad therapeutic repertoire not only greatly improves individualized management of the disease, but also makes choices more complex and difficult. A number of factors must be considered, including disease activity and severity, safety profile, and patient preference. We here discuss the currently existing options and suggest treatment algorithms for managing relapsing-remitting multiple sclerosis.

Contribution of spinal cord biopsy to diagnosis of aquaporin-4 antibody positive neuromyelitis optica spectrum disorder

Longitudinally extensive transverse myelitis is characteristic but not pathognomonic for neuromyelitis optica spectrum disorders (NMOSDs) and may mimic local tumors. In this retrospective study based on a cohort of 175 NMOSD patients we identified seven patients who initially presented with a longitudinally extensive spinal cord lesion and underwent spinal cord biopsy due to magnetic resonance imaging (MRI)-suspected malignancies. Remarkably, routine neuropathology was inconclusive and did not guide the diagnostic process to anti-aquaporin-4 (AQP4)-seropositive NMOSD. Serious postoperative complications occurred in 5/7 patients and persisted during follow-up in 2/7 patients (29%). Considering these sequelae, AQP4-antibody testing should be mandatory in patients with inconclusive longitudinally extensive spinal cord lesions prior to biopsy.

Interferon-β-related tumefactive brain lesion in a Caucasian patient with neuromyelitis optica and clinical stabilization with tocilizumab

BackgroundNeuromyelitis optica (NMO) is a severely disabling inflammatory disorder of the central nervous system and is often misdiagnosed as multiple sclerosis (MS). There is increasing evidence that treatment options shown to be beneficial in MS, including interferon-β (IFN-β), are detrimental in NMO.Case presentationWe here report the first Caucasian patient with aquaporin 4 (AQP4) antibody (NMO-IgG)-seropositive NMO presenting with a tumefactive brain lesion on treatment with IFN-β. Disease started with relapsing optic neuritis and an episode of longitudinally extensive transverse myelitis (LETM) in the absence of any brain MRI lesions or cerebrospinal fluid-restricted oligoclonal bands. After initial misdiagnosis of multiple sclerosis (MS) the patient received subcutaneous IFN-β1b and, subsequently, subcutaneous IFN-β1a therapy for several years. Under this treatment, the patient showed persisting relapse activity and finally presented with a severe episode of subacute aphasia and right-sided hemiparesis due to a large T2 hyperintensive tumefactive lesion of the left brain hemisphere and a smaller T2 lesion on the right side. Despite rituximab therapy two further LETM episodes occurred, resulting in severe neurological deficits. Therapeutic blockade of the interleukin (IL)-6 signalling pathway by tocilizumab was initiated, followed by clinical and radiological stabilization.ConclusionOur case (i) illustrates the relevance of correctly distinguishing NMO and MS since these disorders differ markedly in their responsiveness to immunomodulatory and -suppressive therapies; (ii) confirms and extends a previous report describing the development of tumefactive brain lesions under IFN-β therapy in two Asian NMO patients; and (iii) suggests tocilizumab as a promising therapeutic alternative in highly active NMO disease courses.

Orales Fingolimod bei Multipler Sklerose

ZusammenfassungFingolimod oder FTY720 ist die Leitsubstanz der kürzlich entdeckten Klasse von Sphingosin-1-Phosphat (S1P)-Rezeptor-Modulatoren mit außergewöhnlichen immunregulatorischen Eigenschaften. Mechanistische Studien in Tiermodellen der Multiplen Sklerose (MS) zeigen, dass Fingolimod den Austritt von Immunzellen aus sekundären lymphatischen Organen wie dem Lymphknoten unterbindet und damit die Lymphozytenmigration in entzündetes Zielgewebe verhindert. Tatsächlich belegt eine kürzlich publizierte Phase-III-Studie, dass täglich oral verabreichtes Fingolimod im Vergleich zu Placebo die entzündliche Krankheitsaktivität bei schubförmig-remittierender MS deutlich vermindert und den Verlauf der Erkrankung günstig beeinflusst. Eine weitere Phase-III-Vergleichsstudie zeigt, dass der therapeutische Effekt einer Standardtherapie mit intramuskulär appliziertem Interferon-β1a überlegen ist. Daher ist davon auszugehen, dass Fingolimod in naher Zukunft, möglicherweise zusammen mit Cladribin, als erstes orales Präparat in der MS-Therapie zur Verfügung stehen wird. Zudem legen neueste experimentelle Daten nahe, dass Fingolimod unabhängig von seinen immunmodulatorischen Eigenschaften auch neurale Reparaturmechanismen anstoßen könnte. In dieser Übersicht werden diese rezenten Erkenntnisse zusammengefasst, das immunologische und neurobiologische Profil von Fingolimod dargestellt sowie die vielsprechenden Daten der jüngst veröffentlichten klinischen Studien im Kontext des spezifischen Nebenwirkungsprofils erörtert.SummaryIn this article the recent clinical data on novel therapy of relapsing multiple sclerosis with oral fingolimod (FTY720), lead substance of the recently described class of sphingosine-1-phosphate (S1P) receptor modulators are reviewed. Results of the two phase III studies (FREEDOMS; TRANSFORMS) corroborating previous phase II trial observations suggest that fingolimod has a strong anti-inflammatory effect in relapsing multiple sclerosis (MS), most probably by suppression of lymphocyte re-circulation from lymph nodes to inflammatory tissues (lymphocyte egress). Patients treated with fingolimod show a robust reduction of relapse frequency, compared to placebo (FREEDOMS) or an active comparator (interferon-β1a) (TRANSFORMS) and they show less inflammatory lesions on brain MR imaging. Furthermore, data from experimental research indicate that fingolimod may equally promote neural repair in vivo as well. Thus, the proposed immunological and neurobiological profile of fingolimod as well as the data from the recent clinical trials will be discussed in the context of the expected safety profile.In this article the recent clinical data on novel therapy of relapsing multiple sclerosis with oral fingolimod (FTY720), lead substance of the recently described class of sphingosine-1-phosphate (S1P) receptor modulators are reviewed. Results of the two phase III studies (FREEDOMS; TRANSFORMS) corroborating previous phase II trial observations suggest that fingolimod has a strong anti-inflammatory effect in relapsing multiple sclerosis (MS), most probably by suppression of lymphocyte re-circulation from lymph nodes to inflammatory tissues (lymphocyte egress). Patients treated with fingolimod show a robust reduction of relapse frequency, compared to placebo (FREEDOMS) or an active comparator (interferon-β1a) (TRANSFORMS) and they show less inflammatory lesions on brain MR imaging. Furthermore, data from experimental research indicate that fingolimod may equally promote neural repair in vivo as well. Thus, the proposed immunological and neurobiological profile of fingolimod as well as the data from the recent clinical trials will be discussed in the context of the expected safety profile.

[Oral fingolimod in multiple sclerosis: therapeutic modulation of the sphingosine-1-phosphate system].

ZusammenfassungFingolimod oder FTY720 ist die Leitsubstanz der kürzlich entdeckten Klasse von Sphingosin-1-Phosphat (S1P)-Rezeptor-Modulatoren mit außergewöhnlichen immunregulatorischen Eigenschaften. Mechanistische Studien in Tiermodellen der Multiplen Sklerose (MS) zeigen, dass Fingolimod den Austritt von Immunzellen aus sekundären lymphatischen Organen wie dem Lymphknoten unterbindet und damit die Lymphozytenmigration in entzündetes Zielgewebe verhindert. Tatsächlich belegt eine kürzlich publizierte Phase-III-Studie, dass täglich oral verabreichtes Fingolimod im Vergleich zu Placebo die entzündliche Krankheitsaktivität bei schubförmig-remittierender MS deutlich vermindert und den Verlauf der Erkrankung günstig beeinflusst. Eine weitere Phase-III-Vergleichsstudie zeigt, dass der therapeutische Effekt einer Standardtherapie mit intramuskulär appliziertem Interferon-β1a überlegen ist. Daher ist davon auszugehen, dass Fingolimod in naher Zukunft, möglicherweise zusammen mit Cladribin, als erstes orales Präparat in der MS-Therapie zur Verfügung stehen wird. Zudem legen neueste experimentelle Daten nahe, dass Fingolimod unabhängig von seinen immunmodulatorischen Eigenschaften auch neurale Reparaturmechanismen anstoßen könnte. In dieser Übersicht werden diese rezenten Erkenntnisse zusammengefasst, das immunologische und neurobiologische Profil von Fingolimod dargestellt sowie die vielsprechenden Daten der jüngst veröffentlichten klinischen Studien im Kontext des spezifischen Nebenwirkungsprofils erörtert.SummaryIn this article the recent clinical data on novel therapy of relapsing multiple sclerosis with oral fingolimod (FTY720), lead substance of the recently described class of sphingosine-1-phosphate (S1P) receptor modulators are reviewed. Results of the two phase III studies (FREEDOMS; TRANSFORMS) corroborating previous phase II trial observations suggest that fingolimod has a strong anti-inflammatory effect in relapsing multiple sclerosis (MS), most probably by suppression of lymphocyte re-circulation from lymph nodes to inflammatory tissues (lymphocyte egress). Patients treated with fingolimod show a robust reduction of relapse frequency, compared to placebo (FREEDOMS) or an active comparator (interferon-β1a) (TRANSFORMS) and they show less inflammatory lesions on brain MR imaging. Furthermore, data from experimental research indicate that fingolimod may equally promote neural repair in vivo as well. Thus, the proposed immunological and neurobiological profile of fingolimod as well as the data from the recent clinical trials will be discussed in the context of the expected safety profile.In this article the recent clinical data on novel therapy of relapsing multiple sclerosis with oral fingolimod (FTY720), lead substance of the recently described class of sphingosine-1-phosphate (S1P) receptor modulators are reviewed. Results of the two phase III studies (FREEDOMS; TRANSFORMS) corroborating previous phase II trial observations suggest that fingolimod has a strong anti-inflammatory effect in relapsing multiple sclerosis (MS), most probably by suppression of lymphocyte re-circulation from lymph nodes to inflammatory tissues (lymphocyte egress). Patients treated with fingolimod show a robust reduction of relapse frequency, compared to placebo (FREEDOMS) or an active comparator (interferon-β1a) (TRANSFORMS) and they show less inflammatory lesions on brain MR imaging. Furthermore, data from experimental research indicate that fingolimod may equally promote neural repair in vivo as well. Thus, the proposed immunological and neurobiological profile of fingolimod as well as the data from the recent clinical trials will be discussed in the context of the expected safety profile.