1,720,980 research outputs found
When helpers go above and beyond: characterization of cytotoxic CD4 + T cells in multiple sclerosis
No full textMultiple sclerosis (MS) is the most common neurological disorder in young adults,
and has a huge impact on day-to-day life of patients. MS often limits these persons
in pursuing their dreams and ambitions regarding professional careers, starting a
family, and participating in social activities. While today several treatment options
for especially the early phase of MS exists, no cure is currently available. A specific
type of immune cell, called T cell, is thought to be one of the cells responsible for
development of MS and its progression in time. T cells can be divided into many
subtypes with each its own function. While more and more information has been
gathered on the role of T cells in MS, it is becoming clear that there is a need for new
therapies that can very specifically eliminate the bad types of T cells and leave the
good types of T cells intact.
In this dissertation, I focus on the subset of CD4+ T cells that have cytotoxic properties
(called CD4 CTL), meaning that these cells can directly kill other cells. There is some
evidence in literature that CD4 CTL go to the brain of MS patients, where they can
attack oligodendrocytes. These oligodendrocytesform a protective lining around our
nerves, and death of these cells causes the characteristic symptoms of MS like
numbness, fatigue, weakness, and loss of vision. In this work, CD4 CTL are studied in
great detail to uncover specific features of these cells, which might be specifically
targeted in new therapies. It is found that several types of CD4 CTL exist, with some
types better equipped to cause damages than others. Additionally, CD4 CTL are
shown to be able to leave the blood circulation and reach the brain of MS patients.
Some evidence is presented that two markers in particular, called CRTAM and
Eomes, might be responsible for this. Furthermore, CD4 CTL are found to be
insensitive to Tregs, another type of T cells that normally keep other immune cells in
check and prevent them from harmful overreacting. CD4 CTL themselves interact
with other T cells to make these cells more capable of causing inflammation.
Considering all this information together, this dissertation provides insights into how
CD4 CTL have the potential to cause or worsen MS. Future research should be
conducted to confirm that specific subtypes of CD4 CTL, to be recognized by markers
like CRTAM, Eomes, and specific cytotoxic molecules, can be targeted with new
therapies to limit disease progression of MS patients.Multiple sclerose (MS) is de meest voorkomende neurologische aandoening bij
jongvolwassenen, met een heftige impact op het dagelijkse leven van patiënten. Zij
worden hierdoor vaak beperkt in het najagen van hun ambities en dromen op het
gebied van werk, familieleven en sociale activiteiten. Ondanks dat er momenteel
meerdere behandelingen voor MS beschikbaar zijn, is er nog geen geneesmiddel
voor MS. Een specifieke soort immuuncel, genaamd de T-cel, lijkt een van de cellen
te zijn die verantwoordelijk is voor het ontstaan en verergeren van MS. T-cellen
kunnen onderverdeeld worden in vele verschillende soorten, elk met hun eigen
specifieke rol. Nu er meer en meer informatie beschikbaar komt over de rol van Tcellen in MS, wordt het steeds duidelijker dat het nodig zal zijn om nieuwe
medicijnen te ontwikkelen die heel specifiek de slechte T-cellen kunnen vernietigen,
en de goede T-cellen met rust laten.
In dit proefschrift onderzoek ik een subset van CD4+ T-cellen die cytotoxische
capaciteiten heeft, dit wil zeggen dat deze cellen andere cellen direct kunnen doden.
Deze cellen worden ook wel CD4 CTL genoemd. Er bestaan reeds aanwijzingen dat
CD4 CTL naar de hersenen van MS-patiënten kunnen gaan, en daar oligodendrocyten
kunnen doden. Oligodendrocyten zijn cellen die een beschermende laag rondom
onze zenuwen vormen, en als deze cellen dood gaan zorgt dat voor de
karakteristieke symptomen van MS zoals tintelingen of een doof gevoel,
vermoeidheid, krachtverlies en oogproblemen. In dit project zijn CD4 CTL op
detailniveau bestudeerd en beschreven om nieuwe kenmerken te vinden die heel
specifiek zijn voor deze cellen, zodat deze kenmerken gebruikt kunnen worden om
nieuwe medicijnen te ontwikkelen. Hieruit blijkt dat verschillende soorten CD4 CTL
bestaan, waarvan sommige soorten meer in staat lijken te zijn om schade aan andere
cellen aan te brengen. Daarnaast wordt aangetoond dat CD4 CTL in staat zijn om de
bloedsomloop te verlaten en in de hersenen van MS patiënten binnen te dringen. Er
worden eerste bewijzen getoond dat dit mogelijk te wijten is aan twee specifieke
merkers, CRTAM en Eomes genaamd. Ook is gevonden dat CD4 CTL ongevoelig zijn
voor Tregs, dit is een specifieke soort T-cellen die er speciaal op gericht is om andere
immuun cellen in toom te houden en te voorkomen dat deze schade veroorzaken
door te sterke ontstekingsreacties. CD4 CTL zorgen er daarnaast zelf voor dat andere
T-cellen erger reageren tijdens ontstekingen. Al deze informatie tezamen geven
meer inzicht in de manieren waarop CD4 CTL in staat zijn om een rol te spelen bij het
ontstaan of verergeren van MS. Toekomstig onderzoek is nodig om te bevestigen dat
specifieke subtypes van CD4 CTL, aangeduid door CRTAM, Eomes en specifieke
cytotoxische moleculen, met nieuwe medicaties aangepakt kunnen worden om zo
het ziekteproces van MS te beperken
When helpers go above and beyond: characterization of cytotoxic CD4 + T cells in multiple sclerosis
No full textMultiple sclerosis (MS) is the most common neurological disorder in young adults,
and has a huge impact on day-to-day life of patients. MS often limits these persons
in pursuing their dreams and ambitions regarding professional careers, starting a
family, and participating in social activities. While today several treatment options
for especially the early phase of MS exists, no cure is currently available. A specific
type of immune cell, called T cell, is thought to be one of the cells responsible for
development of MS and its progression in time. T cells can be divided into many
subtypes with each its own function. While more and more information has been
gathered on the role of T cells in MS, it is becoming clear that there is a need for new
therapies that can very specifically eliminate the bad types of T cells and leave the
good types of T cells intact.
In this dissertation, I focus on the subset of CD4+ T cells that have cytotoxic properties
(called CD4 CTL), meaning that these cells can directly kill other cells. There is some
evidence in literature that CD4 CTL go to the brain of MS patients, where they can
attack oligodendrocytes. These oligodendrocytesform a protective lining around our
nerves, and death of these cells causes the characteristic symptoms of MS like
numbness, fatigue, weakness, and loss of vision. In this work, CD4 CTL are studied in
great detail to uncover specific features of these cells, which might be specifically
targeted in new therapies. It is found that several types of CD4 CTL exist, with some
types better equipped to cause damages than others. Additionally, CD4 CTL are
shown to be able to leave the blood circulation and reach the brain of MS patients.
Some evidence is presented that two markers in particular, called CRTAM and
Eomes, might be responsible for this. Furthermore, CD4 CTL are found to be
insensitive to Tregs, another type of T cells that normally keep other immune cells in
check and prevent them from harmful overreacting. CD4 CTL themselves interact
with other T cells to make these cells more capable of causing inflammation.
Considering all this information together, this dissertation provides insights into how
CD4 CTL have the potential to cause or worsen MS. Future research should be
conducted to confirm that specific subtypes of CD4 CTL, to be recognized by markers
like CRTAM, Eomes, and specific cytotoxic molecules, can be targeted with new
therapies to limit disease progression of MS patients.Multiple sclerose (MS) is de meest voorkomende neurologische aandoening bij
jongvolwassenen, met een heftige impact op het dagelijkse leven van patiënten. Zij
worden hierdoor vaak beperkt in het najagen van hun ambities en dromen op het
gebied van werk, familieleven en sociale activiteiten. Ondanks dat er momenteel
meerdere behandelingen voor MS beschikbaar zijn, is er nog geen geneesmiddel
voor MS. Een specifieke soort immuuncel, genaamd de T-cel, lijkt een van de cellen
te zijn die verantwoordelijk is voor het ontstaan en verergeren van MS. T-cellen
kunnen onderverdeeld worden in vele verschillende soorten, elk met hun eigen
specifieke rol. Nu er meer en meer informatie beschikbaar komt over de rol van Tcellen in MS, wordt het steeds duidelijker dat het nodig zal zijn om nieuwe
medicijnen te ontwikkelen die heel specifiek de slechte T-cellen kunnen vernietigen,
en de goede T-cellen met rust laten.
In dit proefschrift onderzoek ik een subset van CD4+ T-cellen die cytotoxische
capaciteiten heeft, dit wil zeggen dat deze cellen andere cellen direct kunnen doden.
Deze cellen worden ook wel CD4 CTL genoemd. Er bestaan reeds aanwijzingen dat
CD4 CTL naar de hersenen van MS-patiënten kunnen gaan, en daar oligodendrocyten
kunnen doden. Oligodendrocyten zijn cellen die een beschermende laag rondom
onze zenuwen vormen, en als deze cellen dood gaan zorgt dat voor de
karakteristieke symptomen van MS zoals tintelingen of een doof gevoel,
vermoeidheid, krachtverlies en oogproblemen. In dit project zijn CD4 CTL op
detailniveau bestudeerd en beschreven om nieuwe kenmerken te vinden die heel
specifiek zijn voor deze cellen, zodat deze kenmerken gebruikt kunnen worden om
nieuwe medicijnen te ontwikkelen. Hieruit blijkt dat verschillende soorten CD4 CTL
bestaan, waarvan sommige soorten meer in staat lijken te zijn om schade aan andere
cellen aan te brengen. Daarnaast wordt aangetoond dat CD4 CTL in staat zijn om de
bloedsomloop te verlaten en in de hersenen van MS patiënten binnen te dringen. Er
worden eerste bewijzen getoond dat dit mogelijk te wijten is aan twee specifieke
merkers, CRTAM en Eomes genaamd. Ook is gevonden dat CD4 CTL ongevoelig zijn
voor Tregs, dit is een specifieke soort T-cellen die er speciaal op gericht is om andere
immuun cellen in toom te houden en te voorkomen dat deze schade veroorzaken
door te sterke ontstekingsreacties. CD4 CTL zorgen er daarnaast zelf voor dat andere
T-cellen erger reageren tijdens ontstekingen. Al deze informatie tezamen geven
meer inzicht in de manieren waarop CD4 CTL in staat zijn om een rol te spelen bij het
ontstaan of verergeren van MS. Toekomstig onderzoek is nodig om te bevestigen dat
specifieke subtypes van CD4 CTL, aangeduid door CRTAM, Eomes en specifieke
cytotoxische moleculen, met nieuwe medicaties aangepakt kunnen worden om zo
het ziekteproces van MS te beperken
When Helpers Go Above and Beyond: Development and Characterization of Cytotoxic CD4(+) T Cells
No full textOnce regarded as an experimental artefact, cytotoxic CD4(+) T cells (CD4 CTL) are presently recognized as a biologically relevant T cell subset with important functions in anti-viral, anti-tumor, and autoimmune responses. Despite the potentially large impact on their micro-environment, the absolute cell counts of CD4 CTL within the peripheral circulation are relatively low. With the rise of single cell analysis techniques, detection of these cells is greatly facilitated. This led to a renewed appraisal of CD4 CTL and an increased insight into their heterogeneous nature and ontogeny. In this review, we summarize the developmental path from naïve CD4(+) T cells to terminally differentiated CD4 CTL, and present markers that can be used to detect or isolate CD4 CTL and their precursors. Subsets of CD4 CTL and their divergent functionalities are discussed. Finally, the importance of local cues as triggers for CD4 CTL differentiation is debated, posing the question whether CD4 CTL develop in the periphery and migrate to site of inflammation when called for, or that circulating CD4 CTL reflect cells that returned to the circulation following differentiation at the local inflammatory site they previously migrated to. Even though much remains to be learned about this intriguing T cell subset, it is clear that CD4 CTL represent interesting therapeutic targets for several pathologies
Treg-Resistant Cytotoxic CD4+ T Cells Dictate T Helper Cells in Their Vicinity: TH17 Skewing and Modulation of Proliferation
No full textCytotoxic CD4+ T cells (CD4 CTL) are terminally differentiated T helper cells that contribute to autoimmune diseases, such as multiple sclerosis. We developed a novel triple co-culture transwell assay to study mutual interactions between CD4 CTL, conventional TH cells, and regulatory T cells (Tregs) simultaneously. We show that, while CD4 CTL are resistant to suppression by Tregs in vitro, the conditioned medium of CD4 CTL accentuates the suppressive phenotype of Tregs by upregulating IL-10, Granzyme B, CTLA-4, and PD-1. We demonstrate that CD4 CTL conditioned medium skews memory TH cells to a TH17 phenotype, suggesting that the CD4 CTL induce bystander polarization. In our triple co-culture assay, the CD4 CTL secretome promotes the proliferation of TH cells, even in the presence of Tregs. However, when cell−cell contact is established between CD4 CTL and TH cells, the proliferation of TH cells is no longer increased and Treg-mediated suppression is restored. Taken together, our results suggest that when TH cells acquire cytotoxic properties, these Treg-resistant CD4 CTL affect the proliferation and phenotype of conventional TH cells in their vicinity. By creating such a pro-inflammatory microenvironment, CD4 CTL may favor their own persistence and expansion, and that of other potentially pathogenic TH cells, thereby contributing to pathogenic responses in autoimmune disorders
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Full text link“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
Full text linkWe 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
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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