Identification of a second T cell epitore of human proteolipid protein (residues 89–106) recognized by proliferative and cytolytic CD4+ T cells from multiple sclerosis patients

Abstract Background: Multiple sclerosis (MS) is an autoimmune, neurodegenerative disorder with a strong genetic component that acts in a complex interaction with environmental factors for disease development. CD4 + T cells are pivotal players in MS pathogenesis, where peripherally activated T cells migrate to the central nervous system leading to demyelination and axonal degeneration. Through a proteomic approach, we aim at identifying dysregulated pathways in activated T cells from MS patients as compared to healthy controls. Methods: CD4 + T cells were purified from peripheral blood from MS patients and healthy controls by magnetic separation. Cells were left unstimulated or stimulated in vitro through the TCR and costimulatory CD28 receptor for 24 hours prior to sampling. Electrospray liquid chromatographytandem mass spectrometry was used to measure protein abundances. Results: Upon T cell activation the abundance of 1,801 proteins was changed. Among these proteins, we observed an enrichment of proteins expressed by MS-susceptibility genes. When comparing protein abundances in T cell samples from healthy controls and MS patients, 18 and 33 proteins were differentially expressed in unstimulated and stimulated CD4 + T cells, respectively. Moreover, 353 and 304 proteins were identified as proteins exclusively induced upon T cell activation in healthy controls and MS patients, respectively and dysregulation of the Nur77 pathway was observed only in samples from MS patients. Conclusions: Our study highlights the importance of CD4 + T cell activation for MS, as proteins that change in abundance upon T cell activation are enriched for proteins encoded by MS susceptibility genes. The results provide evidence for proteomic disturbances in T cell activation in MS, and pinpoint to dysregulation of the Nur77 pathway, a biological pathway known to limit aberrant effector T cell responses.

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The Worm-Specific Immune Response in Multiple Sclerosis Patients Receiving Controlled Trichuris suis Ova Immunotherapy

Life ◽

10.3390/life11020101 ◽

2021 ◽

Vol 11 (2) ◽

pp. 101

Author(s):

Ivet A. Yordanova ◽

Friederike Ebner ◽

Axel Ronald Schulz ◽

Svenja Steinfelder ◽

Berit Rosche ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

T Cell ◽

Clinical Efficacy ◽

Mononuclear Cells ◽

Phase 1 ◽

Th2 Cells ◽

Continuous Increase ◽

Trichuris Suis ◽

Multiple Sclerosis Patients

Considering their potent immunomodulatory properties, therapeutic applications of Trichuris suis ova (TSO) are studied as potential alternative treatment of autoimmune disorders like multiple sclerosis (MS), rheumatoid arthritis (RA), or inflammatory bowel disease (IBD). Clinical phase 1 and 2 studies have demonstrated TSO treatment to be safe and well tolerated in MS patients, however, they reported only modest clinical efficacy. We therefore addressed the cellular and humoral immune responses directed against parasite antigens in individual MS patients receiving controlled TSO treatment (2500 TSO p.o. every 2 weeks for 12 month). Peripheral blood mononuclear cells (PBMC) of MS patients treated with TSO (n = 5) or placebo (n = 6) were analyzed. A continuous increase of serum IgG and IgE antibodies specific for T. suis excretory/secretory antigens was observed up to 12 months post-treatment. This was consistent with mass cytometry analysis identifying an increase of activated HLA-DRhigh plasmablast frequencies in TSO-treated patients. While stable and comparable frequencies of total CD4+ and CD8+ T cells were detected in placebo and TSO-treated patients over time, we observed an increase of activated HLA-DR+CD4+ T cells in TSO-treated patients only. Frequencies of Gata3+ Th2 cells and Th1/Th2 ratios remained stable during TSO treatment, while Foxp3+ Treg frequencies varied greatly between individuals. Using a T. suis antigen-specific T cell expansion assay, we also detected patient-to-patient variation of antigen-specific T cell recall responses and cytokine production. In summary, MS patients receiving TSO treatment established a T. suis-specific T- and B-cell response, however, with varying degrees of T cell responses and cellular functionality across individuals, which might account for the overall miscellaneous clinical efficacy in the studied patients.

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T cell vaccination in multiple sclerosis patients with autologous CSF-derived activated T cells: results from a pilot study

Clinical & Experimental Immunology ◽

10.1046/j.1365-2249.2003.02019.x ◽

2003 ◽

Vol 131 (1) ◽

pp. 155-168 ◽

Cited By ~ 36

Author(s):

A. VAN DER AA ◽

N. HELLINGS ◽

R. MEDAER ◽

G. GELIN ◽

Y. PALMERS ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

T Cell ◽

Pilot Study ◽

Activated T Cells ◽

T Cell Vaccination ◽

Multiple Sclerosis Patients

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Aberrant expression of β-catenin in CD4+ T cells isolated from primary progressive multiple sclerosis patients

Neuroscience Letters ◽

10.1016/j.neulet.2017.05.057 ◽

2017 ◽

Vol 653 ◽

pp. 159-162 ◽

Cited By ~ 2

Author(s):

Sabrina Giacoppo ◽

Oxana Bereshchenko ◽

Stefano Bruscoli ◽

Carlo Riccardi ◽

Placido Bramanti ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Cd4 T Cells ◽

Progressive Multiple Sclerosis ◽

Primary Progressive Multiple Sclerosis ◽

Aberrant Expression ◽

Primary Progressive ◽

Multiple Sclerosis Patients

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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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CD4+ T cells from multiple sclerosis patients respond to a commensal-derived antigen

Annals of Clinical and Translational Neurology ◽

10.1002/acn3.465 ◽

2017 ◽

Vol 4 (11) ◽

pp. 825-829 ◽

Cited By ~ 6

Author(s):

Joseph N. Burgess ◽

Anudeep B. Pant ◽

Lloyd H. Kasper ◽

Sara Colpitts Brass

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Cd4 T Cells ◽

Multiple Sclerosis Patients

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Relationship between Multiple Sclerosis-Associated IL2RA Risk Allele Variants and Circulating T Cell Phenotypes in Healthy Genotype-Selected Controls

Cells ◽

10.3390/cells8060634 ◽

2019 ◽

Vol 8 (6) ◽

pp. 634 ◽

Cited By ~ 4

Author(s):

Sophie Buhelt ◽

Helle Bach Søndergaard ◽

Annette Oturai ◽

Henrik Ullum ◽

Marina Rode von Essen ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Interleukin 2 ◽

T Cell Subsets ◽

Multiparameter Flow Cytometry ◽

Risk Genotype ◽

Increased Risk ◽

New Findings

Single nucleotide polymorphisms (SNPs) in or near the IL2RA gene, that encodes the interleukin-2 (IL-2) receptor α (CD25), are associated with increased risk of immune-mediated diseases including multiple sclerosis (MS). We investigated how the MS-associated IL2RA SNPs rs2104286 and rs11256593 are associated with CD25 expression on T cells ex vivo by multiparameter flow cytometry in paired genotype-selected healthy controls. We observed that MS-associated IL2RA SNPs rs2104286 and rs11256593 are associated with expression of CD25 in CD4+ but not CD8+ T cells. In CD4+ T cells, carriers of the risk genotype had a reduced frequency of CD25+ TFH1 cells (p = 0.001) and an increased frequency of CD25+ recent thymic emigrant cells (p = 0.006). Furthermore, carriers of the risk genotype had a reduced surface expression of CD25 in post-thymic expanded CD4+ T cells (CD31−CD45RA+), CD39+ TReg cells and in several non-follicular memory subsets. Our study found novel associations of MS-associated IL2RA SNPs on expression of CD25 in CD4+ T cell subsets. Insight into the associations of MS-associated IL2RA SNPs, as these new findings provide, offers a better understanding of CD25 variation in the immune system and can lead to new insights into how MS-associated SNPs contribute to development of MS.

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Modulation of the central memory and Tr1-like regulatory T cells in multiple sclerosis patients responsive to interferon-beta therapy

Multiple Sclerosis Journal ◽

10.1177/1352458511427720 ◽

2011 ◽

Vol 18 (6) ◽

pp. 788-798 ◽

Cited By ~ 13

Author(s):

M Chiarini ◽

F Serana ◽

C Zanotti ◽

R Capra ◽

S Rasia ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Interferon Beta ◽

Central Memory ◽

T Cell Subsets ◽

Individual Treatment ◽

Cell Phenotype ◽

Multiple Sclerosis Patients

Background: Interferon-beta is used to reduce disease activity in multiple sclerosis, but its action is incompletely understood, individual treatment response varies among patients, and biological markers predicting clinical benefits have yet to be identified. Since it is known that multiple sclerosis patients have a deficit of the regulatory T-cell subsets, we investigated whether interferon-beta therapy induced modifications of the two main categories of regulatory T cells (Tregs), natural and IL-10-secreting inducible Tr1 subset, in patients who are biologically responsive to the therapy. Methods: T-cell phenotype was determined by flow cytometry, while real-time PCR was used to evaluate interferon-beta bioactivity through MxA determination, and to measure the RNA for IL-10 and CD46 molecule in peripheral blood mononuclear cells stimulated with anti-CD46 and anti-CD3 monoclonal antibodies, which are known to expand a Tr1-like population. Results: Interferon-beta induced a redistribution of natural Treg subsets with a shift of naive Tregs towards the ‘central memory-like’ Treg population that expresses the CCR7 molecule required for the in vivo suppressive activity. Furthermore, in a subgroup of treated patients, the CD46/CD3 co-stimulation, probably through the Tr1-like subset modulation, increased the production of RNA for IL-10 and CD46. The same group showed a lower median EDSS score after two years of therapy. Conclusions: The selective increase of ‘central memory-like’ subset and the involvement of the Tr1-like population may be two of the mechanisms by which interferon-beta achieves its beneficial effects. The quantification of RNA for IL-10 and CD46 could be used to identify patients with a different response to interferon-beta therapy.

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