Endothelin-1 contributes to the development of virus-induced demyelinating disease

Abstract Background Experimental autoimmune encephalitis (EAE) and virally induced demyelinating disease are two major experimental model systems used to study human multiple sclerosis. Although endothelin-1 level elevation was previously observed in the CNS of mice with EAE and viral demyelinating disease, the potential role of endothelin-1 in the development of these demyelinating diseases is unknown. Methods and results In this study, the involvement of endothelin-1 in the development and progression of demyelinating diseases was investigated using these two experimental models. Administration of endothelin-1 significantly promoted the progression of both experimental diseases accompanied with elevated inflammatory T cell responses. In contrast, administration of specific endothelin-1 inhibitors (BQ610 and BQ788) significantly inhibited progression of these diseases accompanied with reduced T cell responses to the respective antigens. Conclusions These results strongly suggest that the level of endothelin-1 plays an important role in the pathogenesis of immune-mediated CNS demyelinating diseases by promoting immune responses.

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T cell response to two immunodominant proteolipid protein (PLP) peptides in multiple sclerosis patients and healthy controls

Multiple Sclerosis Journal ◽

10.1177/135245859600100503 ◽

1996 ◽

Vol 1 (5) ◽

pp. 270-278 ◽

Cited By ~ 26

Author(s):

CM Pelfrey ◽

LR Tranquill ◽

AB Vogt ◽

HF McFarland

Keyword(s):

Multiple Sclerosis ◽

T Cell ◽

Demyelinating Disease ◽

T Cell Responses ◽

Proteolipid Protein ◽

T Cell Response ◽

Healthy Controls ◽

Cell Responses ◽

Hla Binding ◽

Multiple Sclerosis Patients

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system in which autoimmune T lymphocytes reacting with myelin antigens are believed to play a pathogenic role. Since HLA binding is involved in the selection of T cell responses, we have examined PLP peptide binding to HLA DR2, an HLA allele frequently found in MS patients. Both PLP 40–60 and PLP 89–106 show significant, high affinity binding to HLA DR2. We then tested whether responses to PLP peptides 40–60 and 89–106 are elevated in multiple sclerosis patients compared to matched controls. We also analysed T cell responses to MBP 87–106, which is considered to be the immunodominant region of MBP in humans. Here we demonstrate heterogenous T cell responses to PLP 40–60, PLP 89–106 and MBP 87–106 in both MS patients and controls. The overall number of TCL and the HLA restriction of those TCL did not vary significantly in the two groups. PLP 40–60 specific cytolytic TCL were increased in MS patients, whereas healthy controls had increased percentages of cytolytic TCL responding to PLP 89–106 and MBP 87–106. Although the data presented here shows heterogenous responses in T cell numbers, differences in numbers and specificity of cytolytic cells could be involved in the pathogenesis of autoimmune demyelinating disease.

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Tolerogenic Dendritic Cells Induced by BD750 Ameliorate Proinflammatory T cell Responses and Experimental Autoimmune Encephalitis in Mice

Molecular Medicine ◽

10.2119/molmed.2016.00110 ◽

2017 ◽

Vol 23 (1) ◽

pp. 204-214 ◽

Cited By ~ 4

Author(s):

Yan Zhou ◽

Xiao Leng ◽

Hua Li ◽

Shuxia Yang ◽

Tai Yang ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Autoimmune Encephalitis ◽

T Cell Responses ◽

Experimental Autoimmune Encephalitis ◽

Cell Responses ◽

Tolerogenic Dendritic Cells ◽

Experimental Autoimmune

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Theiler's Virus Infection Induces a Predominant Pathogenic CD4+ T Cell Response to RNA Polymerase in Susceptible SJL/J Mice

Journal of Virology ◽

10.1128/jvi.01398-09 ◽

2009 ◽

Vol 83 (21) ◽

pp. 10981-10992 ◽

Cited By ~ 21

Author(s):

Young-Hee Jin ◽

Bongsu Kang ◽

Byung S. Kim

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Rna Polymerase ◽

Demyelinating Disease ◽

T Cell Responses ◽

T Cell Response ◽

Mouse Strains ◽

Susceptible Mouse ◽

Cell Responses

ABSTRACT Theiler's murine encephalomyelitis virus (TMEV)-induced immune-mediated demyelinating disease in susceptible mouse strains has been extensively investigated as a relevant model for human multiple sclerosis. Previous investigations of antiviral T-cell responses focus on immune responses to viral capsid proteins, while virtually nothing is reported on immune responses to nonstructural proteins. In this study, we have identified noncapsid regions recognized by CD4+ T cells from TMEV-infected mice using an overlapping peptide library. Interestingly, a greater number of CD4+ T cells recognizing an epitope (3D21-36) of the 3D viral RNA polymerase, in contrast to capsid epitopes, were detected in the CNS of TMEV-infected SJL mice, whereas only a minor population of CD4+ T cells from infected C57BL/6 mice recognized this region. The effects of preimmunization and tolerization with these epitopes on the development of demyelinating disease indicated that capsid-specific CD4+ T cells are protective during the early stages of viral infection, whereas 3D21-36-specific CD4+ T cells exacerbate disease development. Therefore, protective versus pathogenic CD4+ T-cell responses directed to TMEV appear to be epitope dependent, and the differences in CD4+ T-cell responses to these epitopes between susceptible and resistant mice may play an important role in the resistance or susceptibility to virally induced demyelinating disease.

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Early IFNγ-Mediated and Late Perforin-Mediated Suppression of Pathogenic CD4 T Cell Responses Are Both Required for Inhibition of Demyelinating Disease by CNS-Specific Autoregulatory CD8 T Cells

Frontiers in Immunology ◽

10.3389/fimmu.2018.02336 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 7

Author(s):

Alexander W. Boyden ◽

Ashley A. Brate ◽

Nitin J. Karandikar

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Demyelinating Disease ◽

T Cell Responses ◽

Cd4 T Cell ◽

Cell Responses

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Therapeutic intervention in relapsing autoimmune demyelinating disease through induction of myelin-specific regulatory CD8 T cell responses

Journal of Translational Autoimmunity ◽

10.1016/j.jtauto.2019.100010 ◽

2019 ◽

Vol 2 ◽

pp. 100010 ◽

Cited By ~ 2

Author(s):

Ashley A. Brate ◽

Alexander W. Boyden ◽

Farah R. Itani ◽

Lecia L. Pewe ◽

John T. Harty ◽

...

Keyword(s):

T Cell ◽

Therapeutic Intervention ◽

Demyelinating Disease ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses

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CTLA-4 blockade in combination with xenogeneic DNA vaccines enhances T-cell responses, tumor immunity and autoimmunity to self antigens in animal and cellular model systems

Vaccine ◽

10.1016/j.vaccine.2003.10.048 ◽

2004 ◽

Vol 22 (13-14) ◽

pp. 1700-1708 ◽

Cited By ~ 88

Author(s):

Polly D. Gregor ◽

Jedd D. Wolchok ◽

Cristina R. Ferrone ◽

Heidi Buchinshky ◽

Jose A. Guevara-Patiño ◽

...

Keyword(s):

T Cell ◽

Tumor Immunity ◽

Dna Vaccines ◽

T Cell Responses ◽

Model Systems ◽

Cellular Model ◽

Cell Responses ◽

Self Antigens

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Genomic profiling of T-cell activation suggests increased sensitivity of memory T cells to CD28 costimulation

Genes and Immunity ◽

10.1038/s41435-020-00118-0 ◽

2020 ◽

Vol 21 (6-8) ◽

pp. 390-408

Author(s):

Dafni A. Glinos ◽

Blagoje Soskic ◽

Cayman Williams ◽

Alan Kennedy ◽

Luke Jostins ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Memory T Cells ◽

T Cell Responses ◽

Model Systems ◽

Open Chromatin ◽

Cell Responses ◽

Cd28 Costimulation

AbstractT-cell activation is a critical driver of immune responses. The CD28 costimulation is an essential regulator of CD4 T-cell responses, however, its relative importance in naive and memory T cells is not fully understood. Using different model systems, we observe that human memory T cells are more sensitive to CD28 costimulation than naive T cells. To deconvolute how the T-cell receptor (TCR) and CD28 orchestrate activation of human T cells, we stimulate cells using varying intensities of TCR and CD28 and profiled gene expression. We show that genes involved in cell cycle progression and division are CD28-driven in memory cells, but under TCR control in naive cells. We further demonstrate that T-helper differentiation and cytokine expression are controlled by CD28. Using chromatin accessibility profiling, we observe that AP1 transcriptional regulation is enriched when both TCR and CD28 are engaged, whereas open chromatin near CD28-sensitive genes is enriched for NF-kB motifs. Lastly, we show that CD28-sensitive genes are enriched in GWAS regions associated with immune diseases, implicating a role for CD28 in disease development. Our study provides important insights into the differential role of costimulation in naive and memory T-cell responses and disease susceptibility.

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