scholarly journals Altered Immune Phenotypes and HLA-DQB1 Gene Variation in Multiple Sclerosis Patients Failing Interferon β Treatment

2021 ◽  
Vol 12 ◽  
Author(s):  
Priyanka Devi-Marulkar ◽  
Carolina Moraes-Cabe ◽  
Pascal Campagne ◽  
Béatrice Corre ◽  
Aida Meghraoui-Kheddar ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Integrated Approach ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Altered Expression ◽  
Gene Variation ◽  
Immune Related Genes ◽  
Nanostring Technology ◽  
Multiple Sclerosis Patients

BackgroundInterferon beta (IFNβ) has been prescribed as a first-line disease-modifying therapy for relapsing-remitting multiple sclerosis (RRMS) for nearly three decades. However, there is still a lack of treatment response markers that correlate with the clinical outcome of patients.AimTo determine a combination of cellular and molecular blood signatures associated with the efficacy of IFNβ treatment using an integrated approach.MethodsThe immune status of 40 RRMS patients, 15 of whom were untreated and 25 that received IFNβ1a treatment (15 responders, 10 non-responders), was investigated by phenotyping regulatory CD4+ T cells and naïve/memory T cell subsets, by measurement of circulating IFNα/β proteins with digital ELISA (Simoa) and analysis of ~600 immune related genes including 159 interferon-stimulated genes (ISGs) with the Nanostring technology. The potential impact of HLA class II gene variation in treatment responsiveness was investigated by genotyping HLA-DRB1, -DRB3,4,5, -DQA1, and -DQB1, using as a control population the Milieu Interieur cohort of 1,000 French healthy donors.ResultsClinical responders and non-responders displayed similar plasma levels of IFNβ and similar ISG profiles. However, non-responders mainly differed from other subject groups with reduced circulating naïve regulatory T cells, enhanced terminally differentiated effector memory CD4+ TEMRA cells, and altered expression of at least six genes with immunoregulatory function. Moreover, non-responders were enriched for HLA-DQB1 genotypes encoding DQ8 and DQ2 serotypes. Interestingly, these two serotypes are associated with type 1 diabetes and celiac disease. Overall, the immune signatures of non-responders suggest an active disease that is resistant to therapeutic IFNβ, and in which CD4+ T cells, likely restricted by DQ8 and/or DQ2, exert enhanced autoreactive and bystander inflammatory activities.

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

2011 ◽  
Vol 18 (6) ◽  
pp. 788-798 ◽  
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.

Intracellular cytokine profile in T-cell subsets of multiple sclerosis patients: different features in primary progressive disease

2001 ◽  
Vol 7 (3) ◽  
pp. 145-150 ◽  
Author(s):  
J Killestein ◽  
B F Den Drijver ◽  
W L Van der Graaff ◽  
B MJ Uitdehaag ◽  
C H Polman ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Peripheral Blood ◽  
T Cell Subsets ◽  
Primary Progressive ◽  
Immunoregulatory Cytokines ◽  
Immune Mediated ◽  
Distinct Disease ◽  
Circulating T Cells ◽  
Multiple Sclerosis Patients

Objective: To evaluate the expression of cytokines in both CD4+ and CD8+ T cells derived from peripheral blood of untreated multiple sclerosis (MS) patients with either relapsing-remitting (RR), secondary progressive (SP) or primary progressive (PP) MS and healthy controls (HC). Background: MS is an immune-mediated disease and cytokines have been hypothesized to contribute significantly to disease progression. Compared to the relapse-onset (RR, SP) form of the disease, PPMS patients have different clinical, immunological and pathological features. Surprisingly, the ability of their circulating T cells to produce immunoregulatory cytokines has not been extensively studied so far. Methods: Seventy-two MS patients (24 RR, 26 SP, 22 PP) and 34 HC were studied. Stimulated peripheral blood derived CD4+ and CD8+ T cells were analyzed for IFN-g, IL-2, TNF-a, IL-4, IL-10 and IL-13 production. Results: MS patients express significantly more CD4+ and CD8+ T cells producing IFN-g compared to HC. Compared to the other forms of the disease, PPMS patients display a significant decrease in CD4+ T cells producing IL-2, IL-13 and TNF-a and a significant increase in CD8+ T cells producing IL-4 and IL-10. Conclusions: The data presented here demonstrate that patients with PPMS express less pro- and more anti-inflammatory cytokine producing T cells compared to the relapse-onset form of the disease, confirming the view on PPMS as a distinct disease entity.

scholarly journals Dimethyl fumarate selectively reduces memory T cells in multiple sclerosis patients

2015 ◽  
Vol 22 (8) ◽  
pp. 1061-1070 ◽  
Author(s):  
Erin E Longbrake ◽  
Michael J Ramsbottom ◽  
Claudia Cantoni ◽  
Laura Ghezzi ◽  
Anne H Cross ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Dendritic Cells ◽  
Memory T Cells ◽  
Absolute Lymphocyte Count ◽  
Dimethyl Fumarate ◽  
Effector Memory ◽  
Myeloid Dendritic Cells ◽  
Cross Sectional ◽  
Multiple Sclerosis Patients

Background:Dimethyl fumarate (DMF) alters the phenotype of circulating immune cells and causes lymphopenia in a subpopulation of treated multiple sclerosis (MS) patients.Objective:To phenotypically characterize circulating leukocytes in DMF-treated MS patients.Methods:Cross-sectional observational comparisons of peripheral blood from DMF-treated MS patients ( n = 17 lymphopenic and n = 24 non-lymphopenic), untreated MS patients ( n = 17) and healthy controls ( n = 23); immunophenotyped using flow cytometry. Longitudinal samples were analyzed for 13 DMF-treated patients.Results:Lymphopenic DMF-treated patients had significantly fewer circulating CD8+and CD4+T cells, CD56dimnatural killer (NK) cells, CD19+B cells and plasmacytoid dendritic cells when compared to controls. CXCR3+and CCR6+expression was disproportionately reduced among CD4+T cells, while the proportion of T-regulatory (T-reg) cells was unchanged. DMF did not affect circulating CD56hiNKcells, monocytes or myeloid dendritic cells. Whether lymphopenic or not, DMF-treated patients had a lower proportion of circulating central and effector memory T cells and concomitant expansion of naïve T cells compared to the controls.Conclusions:DMF shifts the immunophenotypes of circulating T cells, causing a reduction of memory cells and a relative expansion of naïve cells, regardless of the absolute lymphocyte count. This may represent one mechanism of action of the drug. Lymphopenic patients had a disproportionate loss of CD8+T-cells, which may affect their immunocompetence.

HLA-E restricted CD8+ T cell subsets are phenotypically altered in multiple sclerosis patients

2013 ◽  
Vol 20 (7) ◽  
pp. 790-801 ◽  
Author(s):  
Kim Pannemans ◽  
Bieke Broux ◽  
An Goris ◽  
Bénédicte Dubois ◽  
Tom Broekmans ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Subsets ◽  
Regulatory Role ◽  
T And B Cells ◽  
Autoreactive T Cell ◽  
Multiple Sclerosis Patients

Background: The importance of Qa-1 restricted CD8+ T cells in regulating autoreactive T cell responses has been demonstrated in animal models for autoimmune disorders, including multiple sclerosis (MS). Objective: We hypothesize that their human variant, HLA-E restricted CD8+ T cells, fulfills a similar regulatory role in man and that these cells are of importance in MS. Methods: A large cohort of MS patients and healthy controls was genotyped for the two known HLA-E polymorphisms. Flow cytometry was used to determine HLA-E expression kinetics and to phenotype HLA-E restricted CD8+ T cells. Immunohistochemistry was performed to investigate HLA-E expression in the central nervous system (CNS) of MS patients. Results: HLA-E is upregulated on immune cells upon in vitro activation and this upregulation is polymorphism-dependent for T and B cells. T and B cells in lesions of MS patients show enhanced HLA-E expression. Furthermore, NKG2C+CD8+ T cells of MS patients have a significantly lower Foxp3 expression, while NKG2A+CD8+ T cells of MS patients produce higher levels of pro-inflammatory cytokines compared to those of healthy individuals. Conclusion: Our study indicates that the HLA-E system is altered in MS and could play a regulatory role in disease.

scholarly journals T-Cell Specificity Influences Disease Heterogeneity in Multiple Sclerosis

2021 ◽  
Vol 8 (6) ◽  
pp. e1075
Author(s):  
Carolina Cruciani ◽  
Marco Puthenparampil ◽  
Paula Tomas-Ojer ◽  
Ivan Jelcic ◽  
Maria Jose Docampo ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
Transcriptome Analysis ◽  
Cell Subset ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Disease Heterogeneity ◽  
Markers Of Inflammation ◽  
Cell Specificity

Background and ObjectivesEncouraged by the enormous progress that the identification of specific autoantigens added to the understanding of neurologic autoimmune diseases, we undertook here an in-depth study of T-cell specificities in the autoimmune disease multiple sclerosis (MS), for which the spectrum of responsible autoantigens is not fully defined yet. The identification of target antigens in MS is crucial for therapeutic strategies aimed to induce antigen-specific tolerance. In addition, knowledge of relevant T-cell targets can improve our understanding of disease heterogeneity, a hallmark of MS that complicates clinical management.MethodsThe proliferative response and interferon gamma (IFN-γ) release of CSF-infiltrating CD4+ T cells from patients with MS against several autoantigens was used to identify patients with different intrathecal T-cell specificities. Fresh CSF-infiltrating and paired circulating lymphocytes in these patients were characterized in depth by ex vivo immunophenotyping and transcriptome analysis of relevant T-cell subsets. Further examination of these patients included CSF markers of inflammation and neurodegeneration and a detailed characterization with respect to demographic, clinical, and MRI features.ResultsBy testing CSF-infiltrating CD4+ T cells from 105 patients with MS against seven long-known myelin and five recently described GDP-l-fucose synthase peptides, we identified GDP-l-fucose synthase and myelin oligodendrocyte glycoprotein (35-55) responder patients. Immunophenotyping of CSF and paired blood samples in these patients revealed a significant expansion of an effector memory (CCR7− CD45RA−) CD27− Th1 CD4+ cell subset in GDP-l-fucose synthase responders. Subsequent transcriptome analysis of this subset demonstrated expression of Th1 and cytotoxicity-associated genes. Patients with different intrathecal T-cell specificities also differ regarding inflammation- and neurodegeneration-associated biomarkers, imaging findings, expression of HLA class II alleles, and seasonal distribution of the time of the lumbar puncture.DiscussionOur observations reveal an association between autoantigen reactivity and features of disease heterogeneity that strongly supports an important role of T-cell specificity in MS pathogenesis. These data have the potential to improve patient classification in clinical practice and to guide the development of antigen-specific tolerization strategies.

scholarly journals Multiple sclerosis patients have reduced resting and increased activated CD4+CD25+FOXP3+T regulatory cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nirupama D. Verma ◽  
Andrew D. Lam ◽  
Christopher Chiu ◽  
Giang T. Tran ◽  
Bruce M. Hall ◽  
...  
Keyword(s):  
T Cells ◽  
T Regulatory Cells ◽  
Mononuclear Cells ◽  
Effector Memory ◽  
Regulatory Cells ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Treg Population ◽  
Multiple Sclerosis Patients ◽  
Population Iii

AbstractResting and activated subpopulations of CD4+CD25+CD127loT regulatory cells (Treg) and CD4+CD25+CD127+ effector T cells in MS patients and in healthy individuals were compared. Peripheral blood mononuclear cells isolated using Ficoll Hypaque were stained with monoclonal antibodies and analysed by flow cytometer. CD45RA and Foxp3 expression within CD4+ cells and in CD4+CD25+CD127loT cells identified Population I; CD45RA+Foxp3+, Population II; CD45RA−Foxp3hi and Population III; CD45RA−Foxp3+ cells. Effector CD4+CD127+ T cells were subdivided into Population IV; memory /effector CD45RA− CD25−Foxp3− and Population V; effector naïve CD45RA+CD25−Foxp3−CCR7+ and terminally differentiated RA+ (TEMRA) effector memory cells. Chemokine receptor staining identified CXCR3+Th1-like Treg, CCR6+Th17-like Treg and CCR7+ resting Treg. Resting Treg (Population I) were reduced in MS patients, both in untreated and treated MS compared to healthy donors. Activated/memory Treg (Population II) were significantly increased in MS patients compared to healthy donors. Activated effector CD4+ (Population IV) were increased and the naïve/ TEMRA CD4+ (Population V) were decreased in MS compared to HD. Expression of CCR7 was mainly in Population I, whereas expression of CCR6 and CXCR3 was greatest in Populations II and intermediate in Population III. In MS, CCR6+Treg were lower in Population III. This study found MS is associated with significant shifts in CD4+T cells subpopulations. MS patients had lower resting CD4+CD25+CD45RA+CCR7+ Treg than healthy donors while activated CD4+CD25hiCD45RA−Foxp3hiTreg were increased in MS patients even before treatment. Some MS patients had reduced CCR6+Th17-like Treg, which may contribute to the activity of MS.

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

Life ◽  
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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