1,720,973 research outputs found
MicroRNA-92a–CPEB3 axis protects neurons against inflammatory neurodegeneration
No full textNeuroinflammation causes neuronal injury in multiple sclerosis (MS) and other neurological diseases. MicroRNAs (miRNAs) are important modulators of neuronal stress responses, but knowledge about their contribution to neuronal protection or damage during inflammation is limited. Here, we constructed a regulatory miRNA–mRNA network of inflamed motor neurons by leveraging cell type–specific miRNA and mRNA sequencing of mice undergoing experimental autoimmune encephalomyelitis (EAE). We found robust induction of miR-92a in inflamed spinal cord neurons and identified cytoplasmic polyadenylation element-binding protein 3 ( Cpeb3 ) as a key target of miR-92a–mediated posttranscriptional silencing. We detected CPEB3 repression in inflamed neurons in murine EAE and human MS. Moreover, both miR-92a delivery and Cpeb3 deletion protected neuronal cultures against excitotoxicity. Supporting a detrimental effect of Cpeb3 in vivo, neuron-specific deletion in conditional Cpeb3 knockout animals led to reduced inflammation-induced clinical disability in EAE. Together, we identified a neuroprotective miR-92a– Cpeb3 axis in neuroinflammation that might serve as potential treatment target to limit inflammation-induced neuronal damage.By constructing miRNA–mRNA networks in neurons a miR-92a–Cpeb3 axis was discovered that protects from neuroinflammation
Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy
No full textPregnancy is one of the strongest inducers of immunological tolerance. Disease activity of many autoimmune diseases including multiple sclerosis (MS) is temporarily suppressed by pregnancy, but little is known about the underlying molecular mechanisms. Here, we investigated the endocrine regulation of conventional and regulatory T cells (Tregs) during reproduction. In vitro, we found the pregnancy hormone progesterone to robustly increase Treg frequencies via promiscuous binding to the glucocorticoid receptor (GR) in T cells. In vivo, T-cell-specific GR deletion in pregnant animals undergoing experimental autoimmune encephalomyelitis (EAE), the animal model of MS, resulted in a reduced Treg increase and a selective loss of pregnancy-induced protection, whereas reproductive success was unaffected. Our data imply that steroid hormones can shift the immunological balance in favor of Tregs via differential engagement of the GR in T cells. This newly defined mechanism confers protection from autoimmunity during pregnancy and represents a potential target for future therapy
Protective effect of TCR-mediated MAIT cell activation during experimental autoimmune encephalomyelitis
No full textAbstract Mucosal-associated invariant T (MAIT) cells express semi-invariant T cell receptors (TCR) for recognizing bacterial and yeast antigens derived from riboflavin metabolites presented on the non-polymorphic MHC class I-related protein 1 (MR1). Neuroinflammation in multiple sclerosis (MS) is likely initiated by autoreactive T cells and perpetuated by infiltration of additional immune cells, but the precise role of MAIT cells in MS pathogenesis remains unknown. Here, we use experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, and find an accumulation of MAIT cells in the inflamed central nervous system (CNS) enriched for MAIT17 (RORγt + ) and MAIT1/17 (T-bet + RORγt + ) subsets with inflammatory and protective features. Results from transcriptome profiling and Nur77GFP reporter mice show that these CNS MAIT cells are activated via cytokines and TCR. Blocking TCR activation with an anti-MR1 antibody exacerbates EAE, whereas enhancing TCR activation with the cognate antigen, 5-(2-oxopropylideneamino)−6-D-ribitylaminouracil, ameliorates EAE severity, potentially via the induction of amphiregulin (AREG). In summary, our findings suggest that TCR-mediated MAIT cell activation is protective in CNS inflammation, likely involving an induction of AREG.Bundesministerium für Bildung und Forschung https://doi.org/10.13039/501100002347Deutsche Forschungsgemeinschaft https://doi.org/10.13039/50110000165
Progesterone modulates the T‐cell response via glucocorticoid receptor‐dependent pathways
No full textMechanismen der Schwangerschafts-induzierten Toleranz in einem Tiermodell der Multiplen Sklerose
No full textMultiple sclerosis (MS) is the most frequent inflammatory disease affecting the central nervous system (CNS). During pregnancy, MS patients show ameliorated disease activity resulting in decreased relapse rates, while post-partum disease activity is increased before returning to the individual pre-pregnancy rates. Foxp3+ regulatory T cells (Treg), which are expanding during pregnancy and are crucial for establishing tolerance to the semiallogeneic fetus, are hypothesized to play a pivotal role in mediating this pregnancy- associated control of autoimmunity. However, the precise mechanism by which this occurs is currently unknown. Thus, the goal of this work was to investigate the underlying molecular pathways of pregnancy-induced CNS tolerance in a mouse model of MS with a special focus on Treg.
For this purpose, a mouse model of pregnancy-associated CNS tolerance was established. In this model, pregnant mice are temporarily protected from developing experimental autoimmune encephalomyelitis (EAE) and present with reduced CNS infiltration of immune cells. Similar to MS patients, a rebound phenomenon is observed after delivery. Additionally, Treg frequency, phenotype and function were assessed throughout pregnancy and post-partum. Treg preferentially accumulated in uterus-draining lymph nodes and persisted as long as 30 days post-partum. Moreover, late gestational Treg presented elevated expression of Ki67 and Ctla4 and showed increased suppressive capacity. Accumulation of Treg could be emulated in vitro by the pregnancy hormone progesterone (P4). This effect could be attributed to P4 cross-engagement of the glucocorticoid receptor (GR) in T cells. Accordingly, T cell-restricted GR-deficiency in GRfl/flLck-Cre mice abrogated Treg accumulation. Furthermore, the relevance of this mechanism was evaluated in pregnancy in vivo. While GR in T cells was required for pregnancy-induced protection from EAE, it was dispensable for effective reproduction, as the fetal loss rate was unchanged in comparison to control animals. Treg accumulation by GR engagement could be further attributed to differential steroid resistance of Treg and conventional T cells (Tcon), rendering Treg more steroid resistant. Finally, whole genome expression analysis was utilized to identify Cpt1a, Il7r and other target genes potentially involved in rendering the Treg population more resilient during pregnancy.
In summary, this works proposes a role for differential GR-mediated sensitivity of Treg and Tcon to pregnancy-related steroid hormones being dispensable for fetomaternal tolerance but indispensable for pregnancy-induced amelioration of CNS autoimmunity.Multiple Sklerose (MS) ist die häufigste entzündliche Erkrankung des zentralen Nervensystems (ZNS). Während der Schwangerschaft von MS-Patientinnen kommt es zu einer Reduktion der Krankheitsaktivität mit Verminderung der Schubrate. Nach der Geburt des Kindes steigt die Schubrate zunächst sprunghaft an, um sich in der Folge wieder auf das Vor-Schwangerschafts-Niveau einzupendeln. Es wird angenommen, dass Foxp3+ regulatorische T-Zellen (Treg), die während der Schwangerschaft eine immunologische Toleranz gegenüber dem semiallogenen Fetus sicherstellen, am Aufbau dieses temporären Schutzes vor Autoimmunität beteiligt sind. Wie genau dieser Schutz jedoch vermittelt wird, ist bisher nicht ausreichend verstanden. Ziel dieser Arbeit war es daher, die zugrundeliegenden zellulären und molekularen Zusammenhänge in einem Mausmodel der MS unter besonderer Berücksichtigung von Treg zu untersuchen.
Zu diesem Zweck wurde ein Mausmodel etabliert, in dem trächtige Mäuse temporär vor der Entwicklung einer experimentellen autoimmunen Enzephalomyelitis (EAE) geschützt sind und eine verminderte ZNS-Infiltration von Immunzellen aufweisen. Wie bei MS- Patientinnen kommt es nach der Geburt zu einem Rebound-Phänomen. Zusätzlich wurden Frequenz, Phänotyp und Funktion von Treg während der Trächtigkeit und im postpartalen Verlauf untersucht. Treg reicherten sich insbesondere in den Uterus- drainierenden Lymphknoten an und blieben bis 30 Tage postpartum erhöht nachweisbar. Weiterhin zeigten Treg in der späten Trächtigkeit eine erhöhte Expression von Ki67 und Ctla4 und hatten eine erhöhte suppressive Kapazität. Die Anreicherung von Treg konnte in vitro mit dem Schwangerschaftshormon Progesteron (P4) nachgestellt werden. Dieser Effekt konnte ferner auf eine Kreuz-Reaktivität von P4 am Glukokortikoid-Rezeptor (GR) zurückgeführt werden. Insbesondere da eine auf T-Zellen beschränkte GR-Defizienz in GRfl/flLck-Cre-Mäusen die Treg-Anreicherung aufhob. Daraufhin wurde die Bedeutung dieses Mechanismus während der Trächtigkeit in vivo untersucht. Während der GR in T- Zellen unerlässlich für den Trächtigkeits-induzierten Schutz vor EAE war, war er für die Toleranz gegenüber den Feten nicht zwingend notwendig. Die Treg-Anreicherung konnte weiterhin auf eine höhere Steroid-Resistenz von Treg gegenüber konventionellen T-Zellen (Tcon) zurückgeführt werden. Schließlich wurden in eine genomweiten Genexpressionsanalyse Cpt1a, Il7r und weitere Kandidaten identifiziert, die potentiell an einer erhöhten Widerstandkraft von Treg während der Trächtigkeit beteiligt sind.
Zusammenfassend wurde in der vorliegenden Arbeit eine differenzielle GR-vermittelte Sensitivität von Treg und Tcon gegenüber Schwangerschafts-assoziierten Steroidhormonen gezeigt. Dieser Mechanismus war keine zwingende Voraussetzung für die Toleranz gegenüber den Feten, war jedoch andererseits unerlässlich für einen Schwangerschafts-induzierten Schutz vor ZNS-Autoimmunität
a dynamic equilibrium
No full textObgleich der Systemische Lupus Erythematodes (SLE) gewissermaßen als Prototyp
der systemischen Autoimmunerkrankungen gilt, ist seine Pathogenese noch
weitgehend unklar. Von Bedeutung scheint im Rahmen des Auftretens von
Autoantikörpern gegen dsDNA auch eine mangelnde Kontrolle autoreaktiver CD4+ T
-Helfer-Zellen zu sein. Diese vor allem gegen nukleäre Peptidantigene
gerichteten T-Helfer-Zellen können in einer immunologischen Kreuzreaktion die
Produktion von Anti-dsDNA-Antikörpern induzieren. Die Untersuchung
autoreaktiver T-Helfer-Zellen gestaltete sich in der Vergangenheit jedoch
methodisch schwierig. Hauptgrund hierfür ist ihre sehr geringe Frequenz im
periphervenösen Blut. Dies machte lange Stimulationszeiten von mehreren Tagen
erforderlich, um die T-Helfer-Zellen anhand ihrer gesteigerten Proliferation
identifizieren zu können. Mit steigender Stimulationsdauer ergab sich
allerdings die Schwierigkeit, eine ausreichende Spezifität der Messungen
sicherzustellen. Durch Zelluntergang eingetragene nukleäre Antigene (endogene
Kontamination) und der Einfluss von außen eingetragener Verunreinigungen
(exogene Kontamination) brachten die vorhandenen Methoden an die Grenze ihrer
spezifischen Aussagekraft. In dieser Arbeit wird eine leicht zu handhabende
zytometrische Nachweismethode autoreaktiver T-Helfer-Zellen im periphervenösen
Blut von SLE-Patienten vorgestellt. Als Marker für die antigenspezifische
Aktivierung wurde CD40L verwandt. Die Stimulationszeit konnte mit 6 Stunden
wesentlich kürzer gewählt werden als bei den bisherigen Proliferationsassays.
Dies garantiert eine Messung der präformierten autoaggressiven Immunantwort
und umgeht den Spezifitätsverlust durch eine mehrtägige Stimulation. Die
Methode erlaubt im selben Arbeitsgang eine genaue zytometrische
Phänotypisierung der autoaggressiven Zellen, die zudem einer gezielten
Anreicherung und Kultivierung mittels MACS zur Verfügung stehen. Mittels der
CD40L-Expression wurde die autoaggressive T-Helfer-Zell-Antwort in einem
repräsentativen SLE-Kollektiv (n= 41 Blutproben) untersucht. Gegen Nukleosomen
gerichtete T-Helfer-Zellen konnten bei 6/19 (31,6%) der untersuchten Proben
festgestellt werden. Autoreaktive T-Helfer-Zellen gegen das nukleäre
Peptidantigen SmD1(83-119) ließen sich demgegenüber wesentlich seltener
nachweisen 2/41 (4,9%). Weiterhin wurde der Einfluss der regulatorischen
T-Zellen auf die autoaggressive Immunantwort bei 11 Proben mittels einer in
vitro-CD25-Depletion untersucht. Durch die Depletion der Treg-Zellen konnte
eine Steigerung der T-Helfer-Zell-Antwort gegen das SmD1(83-119) Peptid um
46,6% erreicht werden (p=0,05), die sich damit signifikant vom Kontrollniveau
abhebt (p=0,026). Diese demaskierte SmD1(83-119)-Antwort zeigt zudem eine
exzellente Korrelation mit der Krankheitsaktivität gemessen im SLEDAI-Score
(p=0,005; r=0,779) und ist in dieser Untersuchung der beste
Krankheitsaktivitätsmarker. Die Ergebnisse dieser Arbeit unterstreichen die
Bedeutung des dynamischen Gleichgewichtes autoreaktiver und regulatorischer
T-Zellen für die Pathogenese des SLE. Wird die im Rahmen eines
Krankheitsschubs verstärkte autoreaktive Immunantwort nicht effektiv durch die
regulativen T-Zellen beherrscht, kommt es zur autoreaktiven Selbstschädigung.
Die entscheidende Rolle der regulatorischen T-Zellen für die Krankheitsdynamik
im humanen SLE konnte hier erstmals in dieser Form gezeigt werden. Regulative
T-Zellen und das Autoantigen SmD1(83-119)-Peptid stellen vielversprechende
Ansatzpunkte für zukünftige spezifische Immuntherapien dar. Die hier
etablierte Methode zur zytometrischen Messung autoreaktiver T-Helfer-Zellen im
Patientenblut könnte auch in anderen Autoimmunerkrankungen einen direkten
Zugang zur autoaggressiven T-Zell-Antwort ermöglichen.Although systemic lupus erythematosus (SLE) is considered to be a prototype of
a systemic autoimmune disease, its pathogenesis still remains largely unclear.
However, an impaired control of autoreactive CD4+ T helper cells seems to be
important for the tolerance break down as autoreactive T helper cells specific
for nuclear peptide antigens have been shown to induce the production of anti-
dsDNA antibodies. The detection of these autoreactive T helper cells is
limited by their very low frequency in the peripheral venous blood, though.
Accordingly, several days of antigenic stimulation have been required to
efficiently identify T helper cells due to their increased proliferation.
Since long term stimulations are prone to unspecific effects caused by
exogenous culture contamination and endogenous contamination with nuclear
autoantigens liberated in the course of naturally occurring cell death the
significance of these measurements was limited. In this work, a recently
established method of measuring T cell activation by flow cytometry is
advanced for the detection of autoreactive T helper cells in the peripheral
venous blood of SLE patients. As a marker of antigen-specific activation CD40L
(CD154) was used. The considerably shorter stimulation time of six hours
guarantees a detection of the preformed autoaggressive immune response and
avoids the loss of specificity of a long term stimulation. At the same time,
this method enables an exact cytometric phenotyping of the autoaggressive
cells, which are further accessible to their enrichment by MACS. The
autoaggressive T helper cell response was determined according to the
intracellular expression of CD40L in CD4+ T helper cells after stimulation
with SLE-associated autoantigens in a representative SLE collective (n = 41
blood samples). While a autoreactive response to human nucleosomes could be
observed in 6 of 19 (31.6%) samples, autoreactive T helper cells specific for
the SmD1(83-119) peptide were detectable only in 2 of 41 (4.9%) samples. To
determine the influence of regulatory T cells (Tregs) on the activation of
autoaggressive T helper cells, Tregs were removed by depleting CD25+ cells
prior to antigenic stimulation in 11 samples. Due to the removal of Tregs a
significant increase of the SmD1(83-119)-specific T helper cell response could
be achieved (+46.6%, p=0.05). This unmasked SmD1(83-119)-response laid
significantly above the level of the unstimulated controls (p = 0.026).
Furthermore, it strongly correlated with the disease activity as assessed by
the SLEDAI score (p=0.005, r=0.779). The results of this study emphasize the
importance of a dynamic balance of autoreactive and regulatory T cells in the
pathogenesis of SLE. Thus, an ineffective control of the autoreactive immune
response by Tregs can lead to autoreactive self-defeating. Regulatory T cells
and the autoantigen SmD1(83-119) peptide provide promising starting points for
future specific immunotherapies. The direct assessment of autoantigen-specific
CD4+ T helper cells according to the antigen-induced CD154 expression in
combination with a depletion of CD25+ Tregs may be of further use in other
autoimmune diseases
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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