scholarly journals Multiple Sclerosis CD49d+CD154+ As Myelin-Specific Lymphocytes Induced During Remyelination

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 15
Author(s):  
Paweł Piatek ◽  
Magdalena Namiecinska ◽  
Małgorzata Domowicz ◽  
Marek Wieczorek ◽  
Sylwia Michlewska ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cumulative Effect ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Cns Demyelination ◽  
The Brain ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS) mediated by autoreactive lymphocytes. The role of autoreactive lymphocytes in the CNS demyelination is well described, whereas very little is known about their role in remyelination during MS remission. In this study, we identified a new subpopulation of myelin-specific CD49d+CD154+ lymphocytes presented in the peripheral blood of MS patients during remission, that proliferated in vitro in response to myelin peptides. These lymphocytes possessed the unique ability to migrate towards maturing oligodendrocyte precursor cells (OPCs) and synthetize proinflammatory chemokines/cytokines. The co-culture of maturing OPCs with myelin-specific CD49d+CD154+ lymphocytes was characterized by the increase in proinflammatory chemokine/cytokine secretion that was not only a result of their cumulative effect of what OPCs and CD49d+CD154+ lymphocytes produced alone. Moreover, maturing OPCs exposed to exogenous myelin peptides managed to induce CD40-CD154-dependent CD49d+CD154+ lymphocyte proliferation. We confirmed, in vivo, the presence of CD49d+CD154+ cells close to maturating OPCs and remyelinating plaque during disease remission in the MS mouse model (C57Bl/6 mice immunized with MOG35-55) by immunohistochemistry. Three weeks after an acute phase of experimental autoimmune encephalomyelitis, CD49d+/CD154+ cells were found to be co-localized with O4+ cells (oligodendrocyte progenitors) in the areas of remyelination identified by myelin basic protein (MBP) labelling. These data suggested that myelin-specific CD49d+CD154+ lymphocytes present in the brain can interfere with remyelination mediated by oligodendrocytes probably as a result of establishing proinflammatory environment.

scholarly journals Autonomous TNF is critical for in vivo monocyte survival in steady state and inflammation

2017 ◽  
Vol 214 (4) ◽  
pp. 905-917 ◽  
Author(s):  
Yochai Wolf ◽  
Anat Shemer ◽  
Michal Polonsky ◽  
Mor Gross ◽  
Alexander Mildner ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mononuclear Phagocytes ◽  
Autoimmune Encephalomyelitis ◽  
Wild Type Counterpart ◽  
And Function ◽  
Necrosis Factor ◽  
Experimental Autoimmune

Monocytes are circulating mononuclear phagocytes, poised to extravasate to sites of inflammation and differentiate into monocyte-derived macrophages and dendritic cells. Tumor necrosis factor (TNF) and its receptors are up-regulated during monopoiesis and expressed by circulating monocytes, as well as effector monocytes infiltrating certain sites of inflammation, such as the spinal cord, during experimental autoimmune encephalomyelitis (EAE). In this study, using competitive in vitro and in vivo assays, we show that monocytes deficient for TNF or TNF receptors are outcompeted by their wild-type counterpart. Moreover, monocyte-autonomous TNF is critical for the function of these cells, as TNF ablation in monocytes/macrophages, but not in microglia, delayed the onset of EAE in challenged animals and was associated with reduced acute spinal cord infiltration of Ly6Chi effector monocytes. Collectively, our data reveal a previously unappreciated critical cell-autonomous role of TNF on monocytes for their survival, maintenance, and function.

scholarly journals Role of Immune Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

2020 ◽  
Author(s):  
Sarah Dhaiban ◽  
Mena Al-Ani ◽  
Noha Mousaad Elemam ◽  
Mahmood H Al-Aawad ◽  
Zeinab Al-Rawi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Cells ◽  
T Regulatory Cells ◽  
Cell Types ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Chronic Autoimmune Disease ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system (CNS) characterized by varying degrees of demyelination of uncertain etiology, and is associated with specific environmental and genetic factors. Upon recognition of CNS antigens, the immune cells initiate an inflammatory process which leads to destruction and deterioration of the neurons. Innate immune cells such as macrophages, dendritic cells and natural killer cells are known to play critical roles in the pathogenesis of MS. Also, the activation of peripheral CD4+ T cells by CNS antigens leads to their extravasation into the CNS causing damages that exacerbates the disease. This could be accompanied by dysregulation of T regulatory cells and other cell types functions. Experimental autoimmune encephalomyelitis (EAE) is a mouse model used to study the pathophysiology of MS disease. In this review, we highlight the roles of innate and adaptive immune players in the pathogenesis of MS and EAE.

The role of Toll-like receptors in multiple sclerosis and possible targeting for therapeutic purposes

2014 ◽  
Vol 0 (0) ◽  
Author(s):  
Maziar Gooshe ◽  
Amir Hossein Abdolghaffari ◽  
Maria Elsa Gambuzza ◽  
Nima Rezaei
Keyword(s):  
Multiple Sclerosis ◽  
Host Defense ◽  
Toll Like Receptors ◽  
Autoimmune Encephalomyelitis ◽  
Pathological Conditions ◽  
The Central Nervous System ◽  
Chronic Autoimmune Disease ◽  
Ms Therapy ◽  
Experimental Autoimmune

AbstractThe interaction between the immune and nervous systems suggests invaluable mechanisms for several pathological conditions, especially neurodegenerative disorders. Multiple sclerosis (MS) is a potentially disabling chronic autoimmune disease, characterized by chronic inflammation and neurodegenerative pathology of the central nervous system. Toll-like receptors (TLRs) are an important family of receptors involved in host defense and in recognition of invading pathogens. The role of TLRs in the pathogenesis of autoimmune disorders such as MS is only starting to be uncovered. Recent studies suggest an ameliorative role of TLR3 and a detrimental role of other TLRs in the onset and progression of MS and experimental autoimmune encephalomyelitis, a murine model of MS. Thus, modulating TLRs can represent an innovative immunotherapeutic approach in MS therapy. This article outlines the role of these TLRs in MS, also discussing TLR-targeted agonist or antagonists that could be used in the different stages of the disease.

scholarly journals Thrombin Cleavage of Osteopontin Modulates Its Activities in Human CellsIn Vitroand Mouse Experimental Autoimmune EncephalomyelitisIn Vivo

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Elena Boggio ◽  
Chiara Dianzani ◽  
Casimiro Luca Gigliotti ◽  
Maria Felicia Soluri ◽  
Nausicaa Clemente ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Published Data ◽  
Autoimmune Encephalomyelitis ◽  
Thrombin Cleavage ◽  
The Central Nervous System ◽  
Potent Drug ◽  
Fine Tune ◽  
Experimental Autoimmune

Osteopontin is a proinflammatory cytokine and plays a pathogenetic role in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), by recruiting autoreactive T cells into the central nervous system. Osteopontin functions are modulated by thrombin cleavage generating N- and C-terminal fragment, whose individual roles are only partly known. Published data are difficult to compare since they have been obtained with heterogeneous approaches. Interestingly, thrombin cleavage of osteopontin unmasks a cryptic domain of interaction withα4β1integrin that is the main adhesion molecule involved in lymphocyte transmigration to the brain and is the target for natalizumab, the most potent drug preventing relapses. We produced recombinant osteopontin and its N- and C-terminal fragments in an eukaryotic system in order to allow their posttranslational modifications. We investigated,in vitro,their effect on human cells andin vivoin EAE. We found that the osteopontin cleavage plays a key role in the function of this cytokine and that the two fragments exert distinct effects bothin vitroandin vivo. These findings suggest that drugs targeting each fragment may be used to fine-tune the pathological effects of osteopontin in several diseases.

scholarly journals Σχεδιασμός, σύνθεση και αξιολόγηση νανοσωματιδίων με εγκλωβισμό πεπτιδίων των πρωτεινών της μυελίνης

2021 ◽  
Author(s):  
Ηρώ Τριανταφυλλάκου
Keyword(s):  
Multiple Sclerosis ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Glycolic Acid ◽  
Myelin Oligodendrocyte Glycoprotein ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Το αντικείμενο της παρούσας ΔΔ ήταν η ανάπτυξη πολυμερικών νανοσωματιδίων με εγκλωβισμένα πεπτιδικά ανάλογα που εμπλέκονται στην εμφάνιση και εξέλιξη της σκλήρυνσης κατά πλάκας (ΣΚΠ, Multiple Sclerosis, MS), καθώς και η βιολογική αξιολόγηση αυτών. Συγκεκριμένα, αναπτύχθηκαν σωματίδια πολυ(γλυκολικού-γαλακτικού) οξέος [poly(lactic-co-glycolic) acid, PLGA] με εγκλωβισμένα πεπτίδια με βάση τον επίτοπο 35-55 της μυελικής γλυκοπρωτεΐνης των ολιγοδενδριτών (Myelin Oligodendrocyte Glycoprotein, ΜΟG) με βάση την αλληλουχία που συναντάται στους μύες (rMOG), συζευγμένα ή μη με μόρια σακχαριτών. Η σύζευξη των πεπτιδικών αναλόγων με μόρια σακχαριτών όπως η μαννόζη και η γλυκοζαμίνη στόχευσε στην πιθανή αλληλεπίδραση με τους υποδοχείς μαννόζης που βρίσκονται στα δενδριτικά κύτταρα, κύρια αντιγονοπαρουσιαστικά κύτταρα που εμπλέκονται στην ΣΚΠ, με τους οποίους υποδοχείς παρουσιάζουν ισχυρή προσδετική ικανότητα και με σκοπό την ανάπτυξη ανοσοανοχής απέναντι στην νόσο.Η διατριβή περιλαμβάνει τον σχεδιασμό και την ανάπτυξη PLGA νανοσωματιδίων που θα φέρουν εγκλωβισμένα τα πεπτιδικά ανάλογα, παρέχοντας αυξημένη σταθερότητα στα πεπτιδικά ανάλογα και παρέχοντας την δυνατότητα βραδείας αποδέσμευσης από την πολυμερική μήτρα. Τα νανοσωματίδια που αναπτύχθηκαν μελετήθηκαν ως προς τα φυσικοχημικά τους χαρακτηριστικά ώστε να βελτιστοποιηθεί η μεθοδολογία σύνθεσης. Επιπλέον, πραγματοποιήθηκε μελέτη της βραδείας αποδέσμευσης και ποσοτικός προσδιορισμός τόσο της αρχικά εγκλωβισμένης ουσίας όσο και της ημερήσιας αποδέσμευσης σε φυσιολογικό ορό in vitro. Τέλος, τα συντεθειμένα νανοσωματίδια αξιολογήθηκαν βιολογικά in vivo στο πειραματικό μοντέλο της ΣΚΠ, την πειραματική αυτοάνοση εγκεφαλομυελίτιδα (Experimental Autoimmune Encephalomyelitis, EAE) με χρήση δύο μοντέλων ανοσοποίησης, προφυλακτικού και θεραπευτικού σε θηλυκούς μύες του γένους C57BL/6. Οι ιστοί που ελήφθησαν από τους μύες μελετήθηκαν για διηθήσεις και καταστροφές της λευκής ουσίας που οφείλονται στην ασθένεια ενώ μελετήθηκαν και τα επίπεδα κυτταροκινών στον ορό αίματος στα διάφορα στάδια εξέλιξης της νόσου.

scholarly journals IFP35 family proteins promote neuroinflammation and multiple sclerosis

2021 ◽  
Vol 118 (32) ◽  
pp. e2102642118
Author(s):  
Xizhong Jing ◽  
Yongjie Yao ◽  
Danning Wu ◽  
Hao Hong ◽  
Xu Feng ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Immune Cells ◽  
Neutralizing Antibodies ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Multiple Cells ◽  
Excessive Activation ◽  
Experimental Autoimmune

Excessive activation of T cells and microglia represents a hallmark of the pathogenesis of human multiple sclerosis (MS). However, the regulatory molecules overactivating these immune cells remain to be identified. Previously, we reported that extracellular IFP35 family proteins, including IFP35 and NMI, activated macrophages as proinflammatory molecules in the periphery. Here, we investigated their functions in the process of neuroinflammation both in the central nervous system (CNS) and the periphery. Our analysis of clinical transcriptomic data showed that expression of IFP35 family proteins was up-regulated in patients with MS. Additional in vitro studies demonstrated that IFP35 and NMI were released by multiple cells. IFP35 and NMI subsequently triggered nuclear factor kappa B–dependent activation of microglia via the TLR4 pathway. Importantly, we showed that both IFP35 and NMI activated dendritic cells and promoted naïve T cell differentiation into Th1 and Th17 cells. Nmi−/−, Ifp35−/−, or administration of neutralizing antibodies against IFP35 alleviated the immune cells’ infiltration and demyelination in the CNS, thus reducing the severity of experimental autoimmune encephalomyelitis. Together, our findings reveal a hitherto unknown mechanism by which IFP35 family proteins facilitate overactivation of both T cells and microglia and propose avenues to study the pathogenesis of MS.

scholarly journals Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells

2011 ◽  
Vol 208 (11) ◽  
pp. 2291-2303 ◽  
Author(s):  
Kamran Ghoreschi ◽  
Jürgen Brück ◽  
Christina Kellerer ◽  
Caishu Deng ◽  
Haiyan Peng ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Dendritic Cells ◽  
Autoimmune Diseases ◽  
Th2 Cells ◽  
Type Ii ◽  
Autoimmune Encephalomyelitis ◽  
Th Cell ◽  
Experimental Autoimmune

Fumarates improve multiple sclerosis (MS) and psoriasis, two diseases in which both IL-12 and IL-23 promote pathogenic T helper (Th) cell differentiation. However, both diseases show opposing responses to most established therapies. First, we show in humans that fumarate treatment induces IL-4–producing Th2 cells in vivo and generates type II dendritic cells (DCs) that produce IL-10 instead of IL-12 and IL-23. In mice, fumarates also generate type II DCs that induce IL-4–producing Th2 cells in vitro and in vivo and protect mice from experimental autoimmune encephalomyelitis. Type II DCs result from fumarate-induced glutathione (GSH) depletion, followed by increased hemoxygenase-1 (HO-1) expression and impaired STAT1 phosphorylation. Induced HO-1 is cleaved, whereupon the N-terminal fragment of HO-1 translocates into the nucleus and interacts with AP-1 and NF-κB sites of the IL-23p19 promoter. This interaction prevents IL-23p19 transcription without affecting IL-12p35, whereas STAT1 inactivation prevents IL-12p35 transcription without affecting IL-23p19. As a consequence, GSH depletion by small molecules such as fumarates induces type II DCs in mice and in humans that ameliorate inflammatory autoimmune diseases. This therapeutic approach improves Th1- and Th17-mediated autoimmune diseases such as psoriasis and MS by interfering with IL-12 and IL-23 production.

scholarly journals The survival and function of IL-10-producing regulatory B cells are negatively controlled by SLAMF5

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lihi Radomir ◽  
Matthias P. Kramer ◽  
Michal Perpinial ◽  
Nofar Schottlender ◽  
Stav Rabani ◽  
...  
Keyword(s):  
B Cells ◽  
Autoimmune Encephalomyelitis ◽  
Regulatory B Cell ◽  
The Central Nervous System ◽  
Factor C ◽  
And Function ◽  
Human And Mouse ◽  
Experimental Autoimmune

AbstractB cells have essential functions in multiple sclerosis and in its mouse model, experimental autoimmune encephalomyelitis, both as drivers and suppressors of the disease. The suppressive effects are driven by a regulatory B cell (Breg) population that functions, primarily but not exclusively, via the production of IL-10. However, the mechanisms modulating IL-10-producing Breg abundance are poorly understood. Here we identify SLAMF5 for controlling IL-10+ Breg maintenance and function. In EAE, the deficiency of SLAMF5 in B cells causes accumulation of IL10+ Bregs in the central nervous system and periphery. Blocking SLAMF5 in vitro induces both human and mouse IL-10-producing Breg cells and increases their survival with a concomitant increase of a transcription factor, c-Maf. Finally, in vivo SLAMF5 blocking in EAE elevates IL-10+ Breg levels and ameliorates disease severity. Our results suggest that SLAMF5 is a negative moderator of IL-10+ Breg cells, and may serve as a therapeutic target in MS and other autoimmune diseases.

scholarly journals DNA threads released by activated CD4+ T lymphocytes provide autocrine costimulation

2019 ◽  
Vol 116 (18) ◽  
pp. 8985-8994 ◽  
Author(s):  
Massimo Costanza ◽  
Pietro L. Poliani ◽  
Paola Portararo ◽  
Barbara Cappetti ◽  
Silvia Musio ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Sterile Inflammation ◽  
Autoimmune Encephalomyelitis ◽  
Priming Phase ◽  
The Central Nervous System

The extrusion of DNA traps contributes to a key mechanism in which innate immune cells clear pathogens or induce sterile inflammation. Here we provide evidence that CD4+ T cells, a critical regulator of adaptive immunity, release extracellular threads of DNA on activation. These DNA extrusions convey autocrine costimulatory signals to T lymphocytes and can be detected in lymph nodes isolated during the priming phase of experimental autoimmune encephalomyelitis (EAE), a CD4+ T cell-driven mouse model of multiple sclerosis. Pharmacologic inhibition of mitochondrial reactive oxygen species (mtROS) abolishes the extrusion of DNA by CD4+ T cells, reducing cytokine production in vitro and T cell priming against myelin in vivo. Moreover, mtROS blockade during established EAE markedly ameliorates disease severity, dampening autoimmune inflammation of the central nervous system. Taken together, these experimental results elucidate a mechanism of intrinsic immune costimulation mediated by DNA threads released by activated T helper cells, and identify a potential therapeutic target for such disorders as multiple sclerosis, neuromyelitis optica, and CD4+ T cell-mediated disorders.

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