CCL2 induction by 1,25(OH)2D3 in dendritic cells from healthy donors and multiple sclerosis patients

Background: Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. The cause of multiple sclerosis is unknown but there are several evidences that associate the genetic basis of the disease with environmental causes. An important association between viral infection and development of MS is clearly demonstrated. Viruses have a strong impact on innate immune cells. In particular, myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs), are able to respond to viruses and to activate the adaptive immune response. Methods: In this study we mimic viral infection using synthetic single-strand RNA, Resiquimod, and we compared the response of both DC subsets derived from healthy donors and MS patients by characterizing the expression of costimulatory molecules on the DC surface. Results: We found that pDCs from MS patients express higher levels of OX40-L, HLA-DR, and CD86 than healthy donors. Moreover, we found that blood cells from MS patients and healthy donors upon Resiquimod-stimulation are enriched in a subpopulation of pDCs, characterized by a high amount of costimulatory molecules. Conclusion: Overall, these results indicate that activation of pDCs is enhanced in MS, likely due to a latent viral infection, and that costimulatory molecules expressed on pDCs could mediate a protective response against the viral trigger of autoimmunity.

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MAP7 and MUCL1 Are Biomarkers of Vitamin D3-Induced Tolerogenic Dendritic Cells in Multiple Sclerosis Patients

Frontiers in Immunology ◽

10.3389/fimmu.2019.01251 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 1

Author(s):

Juan Navarro-Barriuso ◽

María José Mansilla ◽

Bibiana Quirant-Sánchez ◽

Alicia Ardiaca-Martínez ◽

Aina Teniente-Serra ◽

...

Keyword(s):

Multiple Sclerosis ◽

Dendritic Cells ◽

Vitamin D3 ◽

Tolerogenic Dendritic Cells ◽

Multiple Sclerosis Patients

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Impact of type-I-interferon on monocyte subsets and their differentiation to dendritic cells An in vivo and ex vivo study in multiple sclerosis patients treated with interferon-beta

Journal of Neuroimmunology ◽

10.1016/j.neuroim.2003.10.037 ◽

2003 ◽

Author(s):

F Bergh

Keyword(s):

Multiple Sclerosis ◽

Dendritic Cells ◽

Interferon Beta ◽

Type I Interferon ◽

Ex Vivo ◽

Type I ◽

Monocyte Subsets ◽

Multiple Sclerosis Patients ◽

Ex Vivo Study

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FTY720 (fingolimod) treatment tips the balance towards less immunogenic antigen-presenting cells in patients with multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458515574895 ◽

2015 ◽

Vol 21 (14) ◽

pp. 1811-1822 ◽

Cited By ~ 20

Author(s):

Felix Luessi ◽

Stefan Kraus ◽

Bettina Trinschek ◽

Steffen Lerch ◽

Robert Ploen ◽

...

Keyword(s):

Multiple Sclerosis ◽

Dendritic Cells ◽

Healthy Subjects ◽

Ex Vivo ◽

Antigen Presenting Cells ◽

Direct Effects ◽

Quantitative Analyses ◽

Ifn Γ ◽

Multiple Sclerosis Patients ◽

Antigen Presenting

Objective: We aimed to clarify whether fingolimod has direct effects on antigen-presenting cells in multiple sclerosis patients. Methods: Frequency and phenotype of directly ex vivo dendritic cells and monocytes were analyzed in 43 individuals, including fingolimod-treated and untreated multiple sclerosis patients as well as healthy subjects. These cells were further stimulated with lipopolysaccharide to determine functional effects of fingolimod treatment. Results: Absolute numbers of CD1c+ dendritic cells and monocytes were not significantly reduced in fingolimod-treated patients indicating that fingolimod did not block the migration of antigen-presenting cells to peripheral blood. CD86 was upregulated on CD1c+ dendritic cells and thus their activation was not impaired under fingolimod treatment. Quantitative analyses of gene transcription in cells and protein content in supernatants from ex vivo CD1c+ dendritic cells and monocytes, however, showed lower secretion of TNFα, IL1-β and IL-6 upon lipopolysaccharide-stimulation. These results could be matched with CD4+MOG-specific transgenic T cells exhibiting reduced levels of TNFα and IFN-γ but not IL-4 upon stimulation with murine dendritic cells loaded with MOG, when treated with fingolimod. Conclusions: Our data indicate that fingolimod – apart from trapping lymphocytes in lymph nodes – exerts its disease-modulating activity by rebalancing the immune tolerance networks by modulation of antigen-presenting cells.

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Distinct Expression of Inflammatory Features in T Helper 17 Cells from Multiple Sclerosis Patients

Cells ◽

10.3390/cells8060533 ◽

2019 ◽

Vol 8 (6) ◽

pp. 533 ◽

Cited By ~ 6

Author(s):

Alessia Capone ◽

Manuela Bianco ◽

Gabriella Ruocco ◽

Marco De Bardi ◽

Luca Battistini ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Cd4 T Cells ◽

Th17 Cells ◽

Chronic Inflammatory Disease ◽

T Helper ◽

T Helper 17 ◽

Inflammatory Status ◽

Healthy Donors ◽

Multiple Sclerosis Patients

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). T helper (Th) 17 lymphocytes play a role in the pathogenesis of MS. Indeed, Th17 cells are abundant in the cerebrospinal fluid and peripheral blood of MS patients and promote pathogenesis in the mouse model of MS. To gain insight into the function of Th17 cells in MS, we tested whether Th17 cells polarized from naïve CD4 T cells of healthy donors and MS patients display different features. To this end, we analysed several parameters that typify the Th17 profile during the differentiation process of naïve CD4 T cells obtained from relapsing-remitting (RR)-MS patients (n = 31) and healthy donors (HD) (n = 28). Analysis of an array of cytokines produced by Th17 cells revealed that expression of interleukin (IL)-21, tumour necrosis factor (TNF)-β, IL-2 and IL-1R1 is significantly increased in Th17 cells derived from MS patients compared to healthy donor-derived cells. Interestingly, IL-1R1 expression is also increased in Th17 cells circulating in the blood of MS patients compared to healthy donors. Since IL-2, IL-21, TNF-β, and IL-1R1 play a crucial role in the activation of immune cells, our data indicate that high expression of these molecules in Th17 cells from MS patients could be related to their high inflammatory status.

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Impact of Immunomodulatory Treatment on Leukocyte Cytokine Production in Multiple Sclerosis Patients and Healthy Donors

NeuroImmunoModulation ◽

10.1159/000228913 ◽

2009 ◽

Vol 16 (6) ◽

pp. 385-391 ◽

Cited By ~ 7

Author(s):

Dirk Reske ◽

Anne V. Thomas ◽

Hela-Felicitas Petereit ◽

Gereon R. Fink ◽

Michael Schroeter

Keyword(s):

Multiple Sclerosis ◽

Cytokine Production ◽

Immunomodulatory Treatment ◽

Healthy Donors ◽

Multiple Sclerosis Patients

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Cryopreserved vitamin D3-tolerogenic dendritic cells pulsed with autoantigens as a potential therapy for multiple sclerosis patients

Journal of Neuroinflammation ◽

10.1186/s12974-016-0584-9 ◽

2016 ◽

Vol 13 (1) ◽

Cited By ~ 18

Author(s):

María José Mansilla ◽

Raian Contreras-Cardone ◽

Juan Navarro-Barriuso ◽

Nathalie Cools ◽

Zwi Berneman ◽

...

Keyword(s):

Multiple Sclerosis ◽

Dendritic Cells ◽

Vitamin D3 ◽

Tolerogenic Dendritic Cells ◽

Multiple Sclerosis Patients

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FAS-ligand regulates differential activation-induced cell death of human T-helper 1 and 17 cells in healthy donors and multiple sclerosis patients

Cell Death and Disease ◽

10.1038/cddis.2015.100 ◽

2015 ◽

Vol 6 (5) ◽

pp. e1741-e1741 ◽

Cited By ~ 12

Author(s):

M T Cencioni ◽

S Santini ◽

G Ruocco ◽

G Borsellino ◽

M De Bardi ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cell Death ◽

Autoimmune Diseases ◽

Fas Ligand ◽

Th1 Cells ◽

T Helper ◽

Th Cells ◽

Activation Induced Cell Death ◽

Healthy Donors ◽

Multiple Sclerosis Patients

Abstract Functionally distinct T-helper (Th) subsets orchestrate immune responses. Maintenance of homeostasis through the tight control of inflammatory Th cells is crucial to avoid autoimmune inflammation. Activation-Induced Cell Death (AICD) regulates homeostasis of T cells, and it has never been investigated in human Th cells. We generated stable clones of inflammatory Th subsets involved in autoimmune diseases, such as Th1, Th17 and Th1/17 cells, from healthy donors (HD) and multiple sclerosis (MS) patients and we measured AICD. We find that human Th1 cells are sensitive, whereas Th17 and Th1/17 are resistant, to AICD. In particular, Th1 cells express high level of FAS-ligand (FASL), which interacts with FAS and leads to caspases’ cleavage and ultimately to cell death. In contrast, low FASL expression in Th17 and Th1/17 cells blunts caspase 8 activation and thus reduces cell death. Interestingly, Th cells obtained from healthy individuals and MS patients behave similarly, suggesting that this mechanism could explain the persistence of inflammatory IL-17-producing cells in autoimmune diseases, such as MS, where their generation is particularly substantial.

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Massive Restrain of Cytotoxic B cells in the Peripheral Blood During Fingolimod and Natalizumab Treatments in Multiple Sclerosis Patients

10.21203/rs.3.rs-31940/v1 ◽

2020 ◽

Author(s):

Vinícius de Oliveira Boldrini ◽

Raphael Patrício da Silva Quintiliano ◽

Adriel dos Santos Moraes ◽

Carla Stella ◽

Ana Leda Figueiredo Longhini ◽

...

Keyword(s):

Multiple Sclerosis ◽

B Cells ◽

T Lymphocytes ◽

Peripheral Blood ◽

Antibody Therapy ◽

Healthy Donors ◽

Relapsing Remitting ◽

Anti Cd20 ◽

Multiple Sclerosis Patients

Abstract Background Recently, the success of anti-CD20 monoclonal antibody therapy brought a new light over the role of B cells in multiple sclerosis (MS) pathogenesis. Due to the expression pattern of CD20 during B cells ontogeny, this role seems to be extended beyond the antibodies' production and secretion. Therefore, here we investigated whether not only classical cytotoxic CD8+ T lymphocytes but also non-classical cytotoxic B cells may occur in the peripheral blood from relapsing-remitting MS (RRMS) patients. Methods 104 RRMS patients during different treatment and 58 healthy donors were studied. CD19, GzmB, Runx3 and CD49d expression was assessed by flow cytometry analyses. Results Patients treated with Natalizumab (NTZ) showed an increased percentage of CD8+GzmB+ when compared to other MS therapies, untreated RRMS patients and healthy volunteers. Similarly, and unexpected, massive cytotoxic behavior of B cells CD19+GzmB+ was observed in RRMS patients during Fingolimod (FTY) and NTZ therapies when compared to Glatiramer, Interferonβ, untreated MS patients and healthy donors. Conclusions During different MS treatments, B cells exhibit cytotoxic behavior resembling CD8+ T lymphocytes. This data suggest a possible involvement of “cytotoxic” B cells during MS pathology. Monitoring cytotoxic subsets might become an available marker for the risk of relapses and even for accessing therapeutic effectiveness in MS patients.

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