scholarly journals Effector T Helper Cells Are Selectively Controlled During Pregnancy and Related to a Postpartum Relapse in Multiple Sclerosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Steven C. Koetzier ◽  
Rinze F. Neuteboom ◽  
Annet F. Wierenga-Wolf ◽  
Marie-José Melief ◽  
C. Louk de Mol ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Ex Vivo ◽  
Effector Memory ◽  
Healthy Controls ◽  
T Helper ◽  
Third Trimester ◽  
Serum Samples ◽  
Related Factors ◽  
Th Cells ◽  
Pregnancy And Postpartum

Background: Multiple sclerosis (MS) patients are protected from relapses during pregnancy and have an increased relapse risk after delivery. It is unknown how pregnancy controls disease-contributing CD4+ T helper (Th) cells and whether this differs in MS patients who experience a postpartum relapse. Here, we studied the effector phenotype of Th cells in relation to pregnancy and postpartum relapse occurrence in MS.Methods: Memory skewing and activation of effector Th subsets were analyzed in paired third trimester and postpartum blood of 19 MS patients with and without a postpartum relapse and 12 healthy controls. Ex vivo results were associated with circulating levels of pregnancy-induced hormones and mirrored in vitro by exposing proliferating Th cells to corresponding serum samples.Results: Based on HSNE-guided analyses, we found that effector memory proportions of Th cells were increased in postpartum vs. third trimester samples from MS patients without a postpartum relapse. This was not seen for relapsing patients or healthy controls. CXCR3 was upregulated on postpartum memory Th cells, except for relapsing patients. These changes were verified by adding sera from the same individuals to proliferating Th cells, but did not associate with third trimester cortisol, estradiol or progesterone levels. For relapsing patients, activated memory Th cells of both third trimester and postpartum samples produced higher levels of pro-inflammatory cytokines.Conclusion: Effector Th cells are differentially regulated during pregnancy in MS patients, likely via serum-related factors beyond the studied hormones. The pro-inflammatory state of memory Th cells during pregnancy may predict a postpartum relapse.

Role of IL-17-producing lymphocytes in severity of multiple sclerosis upon natalizumab treatment

2016 ◽  
Vol 23 (4) ◽  
pp. 567-576 ◽  
Author(s):  
Ulrike Bühler ◽  
Vinzenz Fleischer ◽  
Felix Luessi ◽  
Ayman Rezk ◽  
Patrick Belikan ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Peripheral Blood ◽  
T Helper Cells ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Healthy Controls ◽  
T Helper ◽  
Peripheral Blood Mononuclear ◽  
Helper Cells

Objective: Natalizumab is known to prevent T-helper cells entering the central nervous system (CNS). We hypothesize that more pathogenic T-helper cells are present outside the CNS and a possible relationship to disease severity. Methods: Characterization and enrichment of human CD4+IL-17+ cells were performed ex vivo using peripheral blood mononuclear cells from natalizumab-treated relapsing-remitting multiple sclerosis (RRMS) patients ( n = 33), untreated RRMS patients ( n = 13), and healthy controls ( n = 33). Magnetic resonance imaging (MRI) scans were performed routinely for patients. Results: Lymphocytes were elevated in peripheral blood of natalizumab-treated patients compared to untreated patients and healthy controls. Whereas group comparison for CD4+IL-17+ numbers also differed, CD4+IFN-γ+ and CD4+IL-22+ counts were not increased. CD4+IL-17+ cells not only expressed but also secreted IL-17. In natalizumab-treated patients, IL-17+ cell frequency was found to correlate with T1-hypointense lesions, but was not an indicator for rebound activity after treatment discontinuation, except in one patient who experienced a fulminant rebound, and interestingly, in whom the highest IL-17+ cell levels were observed. Conclusion: Increased lymphocytes and CD4+IL-17+ cells in the blood of RRMS patients receiving natalizumab corroborate the drug’s mechanism of action, that is, blocking transmigration to CNS. Correlation between IL-17-expressing lymphocytes and T1-hypointense lesions underlines the important role of these cells in the disease pathology.

AB0105 CHECKPOINT MOLECULES AND PREGNANCY: ENHANCED SPD-L1 PREDICTS FLARE IN RA PREGNANCY AND POSTPARTUM

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1351.1-1352
Author(s):  
A. L. Stefanski ◽  
K. Eriksson ◽  
A. Zbinden ◽  
P. Villiger ◽  
F. Förger
Keyword(s):  
Birth Weight ◽  
Disease Activity ◽  
Pregnancy Outcome ◽  
Preterm Delivery ◽  
Adverse Pregnancy Outcome ◽  
Healthy Controls ◽  
Serum Samples ◽  
Healthy Pregnancy ◽  
Pregnancy And Postpartum ◽  
Adverse Pregnancy

Background:Rheumatoid arthritis (RA) is a female-predominant autoimmune disease that may affect women in childbearing age, making family planning an important issue for their life. There is a need for better understanding the mechanisms modulating RA in pregnancy and develop prognostic marker regarding adverse pregnancy outcome such as reduced birth weight and preterm delivery. As a crucial organ for peripheral tolerance during pregnancy, the placenta is expressing constitutively programmed cell death ligand 1 (PD-L1), major ligand of the inhibitory receptor PD-1 (Zhang et al, 2015). We hypothesize that the PD-1 pathway plays a central inhibitory role in regulating the course of the disease and pregnancy outcome in RA.Objectives:To investigate the relationship between PD-1 pathway, disease activity during pregnancy/postpartum and pregnancy outcome in RA.Methods:We measured soluble PD-1 and PD-L1 levels by ELISA in serum samples of 27 pregnant RA patients and 25 healthy pregnant controls at different time points during pregnancy and postpartum. As for pregnancy controls, we analyzed serum samples from 28 non-pregnant RA patients and 18 non-pregnant healthy controls. The data was analyzed in correlation with disease activity (measured by DAS28-CRP) and pregnancy outcome (defined as preterm delivery and birth weight). Statistics were calculated by Mann-Whitney U test and Wilcoxon test, correlations by Spearman rank test.Results:In healthy pregnancy, sPD-L1 increases significantly in the 1sttrimester (p = 0,0198) and decreases significantly postpartum (p = 0,0029). sPD-L1 values are higher in non-pregnant RA patients compared to non-pregnant healthy controls (p = 0,047) and there are no significant changes during RA pregnancy. Postpartum sPD-L1 values are significantly higher in RA patients compared to healthy controls (p = 0,0014), Fig. 1. Notably, regarding disease activity, we noticed a significant positive correlation between the overall sPD-L1 values in RA and DAS28-CRP (p= 0.0104), Fig. 2. No significant correlation was seen between sPD-L1, birth weight and preterm delivery. For sPD-1 we focused on 3rdtrimester and postpartum, however, there was no difference between healthy controls and RA patients and no correlation with disease activity or pregnancy outcome.Conclusion:In healthy pregnancy, we observed an increase of sPD-L1, which decreases after delivery. This supports the hypothesis, that PD-1 pathway may be involved in shaping the physiological fetal-maternal tolerance. In RA higher sPD-L1 values are measured already in non-pregnant patients compared to healthy controls and there is no physiological decrease postpartum. Intriguing, sPD-L1 correlates positively with RA disease activity, reflecting a possible functional antagonism towards the inhibitory function of membrane bound PD-L1 molecules. However, the detailed function of sPD-L1 need to be further delineated. Nevertheless, sPD-L1 may have the potential to serve as prognostic marker for flares in RA pregnancy. Regarding the rather rarely observed adverse pregnancy outcome, larger cohorts need to be investigated.References:[1]Zhang YH, Tian M, Tang MX et al. Recent Insight into the Role of the PD-1/PD-L1 Pathway in Feto-Maternal Tolerance and Pregnancy. Am J Reprod Immunol. 2015 Sep;74(3):201-8.Disclosure of Interests:Ana-Luisa Stefanski: None declared, Klara Eriksson: None declared, Astrid Zbinden: None declared, Peter Villiger Consultant of: MSD, Abbvie, Roche, Pfizer, Sanofi, Speakers bureau: Roche, MSD, Pfizer, Frauke Förger Grant/research support from: Unrestricted grant from UCB, Consultant of: UCB, GSK, Roche, Speakers bureau: UCB, GSK

Unique gene expression program of human germinal center T helper cells

Blood ◽  
2004 ◽  
Vol 104 (7) ◽  
pp. 1952-1960 ◽  
Author(s):  
Chang H. Kim ◽  
Hyung W. Lim ◽  
Jong R. Kim ◽  
Lusijah Rott ◽  
Peter Hillsamer ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Germinal Center ◽  
Memory T Cells ◽  
Effector Memory ◽  
T Helper ◽  
Th Cells ◽  
Effector Memory T Cells ◽  
Expression Program

Abstract Gene expression profiling was used to compare the gene expression patterns of human germinal center (GC) T helper (Th) cells with other CD4+ T-cell subsets (naive, central, and effector memory T cells). GC-Th cells, specifically localized in germinal centers to help B cells, are distantly related to central and effector memory T cells in global gene expression profiles. GC-Th cells displayed substantial differences in mRNA for adhesion molecules, chemoattractant receptors, and cytokines compared with other populations. Distinct expression of transcriptional factors by GC-Th cells is consistent with the hypothesis that they may be different from other T cells in cell lineage. Interestingly, CXCL13, a critical chemokine for B-cell entry to lymphoid follicles, is one of the most highly up-regulated genes in GC-Th cells. GC-Th cells (but not other T cells) produce and secrete large amounts of functional CXCL13 upon T-cell receptor activation, a process that is dependent on costimulation, requires translation and transcription, and is dramatically enhanced by activation in the presence of GC-B cells. This study revealed for the first time the unique gene expression program of GC-Th cells.

scholarly journals Follicular lymphoma tumor–infiltrating T-helper (TH) cells have the same polyfunctional potential as normal nodal TH cells despite skewed differentiation

Blood ◽  
2011 ◽  
Vol 118 (13) ◽  
pp. 3591-3602 ◽  
Author(s):  
Shannon P. Hilchey ◽  
Alexander F. Rosenberg ◽  
Ollivier Hyrien ◽  
Shelley Secor-Socha ◽  
Matthew R. Cochran ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Follicular Lymphoma ◽  
Critical Role ◽  
Cell Receptor ◽  
Effector Memory ◽  
T Helper ◽  
Th Cells ◽  
Lineage Differentiation ◽  
Th Cell

Abstract The follicular lymphoma (FL) T-cell microenvironment plays a critical role in the biology of this disease. We therefore determined the lineage, differentiation state, and functional potential of FL-infiltrating CD4+ T-helper cells (TH) compared with reactive and normal lymph node (NLN) TH cells. Relative to NLNs, FL cells have decreased proportions of naive and central memory but increased proportions of effector memory TH cells. We further show differences in the distribution and anatomical localization of CXCR5+ TH populations that, on the basis of transcription factor analysis, include both regulatory and follicular helper T cells. On Staphylococcus enterotoxin-B stimulation, which stimulates T cells through the T-cell receptor, requires no processing by APCs, and can overcome regulator T cell-mediated suppression, the proportion of uncommitted primed precursor cells, as well as TH2 and TH17 cells is higher in FL cells than in reactive lymph nodes or NLNs. However, the proportion of TH1 and polyfunctional TH cells (producing multiple cytokines simultaneously) is similar in FL cells and NLNs. These data suggest that, although TH-cell differentiation in FL is skewed compared with NLNs, FL TH cells should have the same intrinsic ability to elicit antitumor effector responses as NLN TH cells when tumor suppressive mechanisms are attenuated.

scholarly journals Natalizumab, Fingolimod and Dimethyl Fumarate Use and Pregnancy-Related Relapse and Disability in Women With Multiple Sclerosis

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012084
Author(s):  
Wei Zhen Yeh ◽  
Putu Ayu Widyastuti ◽  
Anneke Van der Walt ◽  
Jim Stankovich ◽  
Eva Havrdova ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cox Regression ◽  
Dimethyl Fumarate ◽  
Disability Progression ◽  
Third Trimester ◽  
Early Postpartum ◽  
Pregnancy And Postpartum ◽  
Relapsing Remitting ◽  
Effective Option ◽  
Using Data

Objective:To investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort.Methods:Using data from the MSBase Registry, we included pregnancies conceived after 31 Dec 2010 from women with relapsing-remitting MS or clinically isolated syndrome. Predictors of intrapartum relapse, and postpartum relapse and disability progression were determined by clustered logistic regression or Cox regression analyses.Results:We included 1998 pregnancies from 1619 women with MS. Preconception annualized relapse rate (ARR) was 0.29 (95% CI 0.27-0.32), fell to 0.19 (0.14-0.24) in third trimester, and increased to 0.59 (0.51-0.67) in early postpartum. Among women who used fingolimod or natalizumab, ARR before pregnancy was 0.37 (0.28-0.49) and 0.29 (0.22-0.37), respectively, and increased during pregnancy. Intrapartum ARR decreased with preconception dimethyl fumarate use. ARR spiked after delivery across all DMT groups. Natalizumab continuation into pregnancy reduced the odds of relapse during pregnancy (OR 0.76 per month [0.60-0.95], p=0.017). DMT re-initiation with natalizumab protected against postpartum relapse (HR 0.11 [0.04-0.32], p<0.0001). Breastfeeding women were less likely to relapse (HR 0.61 [0.41-0.91], p=0.016). 5.6% of pregnancies were followed by confirmed disability progression, predicted by higher relapse activity in pregnancy and postpartum.Conclusion:Intrapartum and postpartum relapse probabilities increased among women with MS after natalizumab or fingolimod cessation. In women considered to be at high relapse risk, use of natalizumab before pregnancy and continued up to 34 weeks gestation, with early re-initiation after delivery is an effective option to minimize relapse risks. Strategies of DMT use have to be balanced against potential fetal/neonatal complications.

scholarly journals Nitrosative stress parameters and the level of oxidized DNA bases in patients with multiple sclerosis

2021 ◽  
Author(s):  
Vitalijs Borisovs ◽  
Jevgenijs Bodrenko ◽  
Jolanta Kalnina ◽  
Nikolajs Sjakste
Keyword(s):  
Nitric Oxide ◽  
Multiple Sclerosis ◽  
Nitrosative Stress ◽  
Dna Bases ◽  
Thiobarbituric Acid Reactive Substance ◽  
Healthy Controls ◽  
Serum Samples ◽  
Oxidative Stress Biomarkers ◽  
Modified Dna ◽  
Purines And Pyrimidines

Abstract Multiple sclerosis (MS) is a neurodegenerative disease with various factors affecting its etiology. Overproduction of nitric oxide and subsequent lesions of biopolymers are some of the possible causes of the disease. This study aimed to measure the most relevant nitrosative and oxidative stress biomarkers and the level of modified DNA bases in patients with MS. Each parameter was assayed in 25 patients with MS and 25 healthy controls. This study involved detecting blood plasma and serum nitric oxide metabolites by chemiluminescence detector Sievers NOA-280i, malondialdehyde (MDA) measurements with thiobarbituric acid reactive substance (TBARS) assay, detection of oxidized purines and pyrimidines with the enzyme-modified comet assay. Statistical analysis of the results was performed by one-way analysis of variance (ANOVA) and unpaired t test for the comparison of less than three data sets. DNA single-strand breaks, levels of modified purines and pyrimidines, as well as nitrite and nitrate levels in plasma and serum samples, were significantly higher in patients with MS than in healthy controls. On the contrary, MDA levels appeared to be lower in patients with MS.

scholarly journals Signatures of immune reprogramming in anti-CD52 therapy of MS: markers for risk stratification and treatment response

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Laura Bierhansl ◽  
Tobias Ruck ◽  
Steffen Pfeuffer ◽  
Catharina C. Gross ◽  
Heinz Wiendl ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Adverse Events ◽  
Treatment Response ◽  
De Novo ◽  
Ex Vivo ◽  
Phase Iii ◽  
Serum Samples ◽  
Two Phase ◽  
Relapsing Remitting

Abstract Background Multiple sclerosis is one of the most prevalent neurological diseases in young adults affecting over 2 million people worldwide. Alemtuzumab is a highly effective therapy in relapsing remitting MS. Alemtuzumab is a monoclonal CD52 antibody that proved its efficacy against an active comparator (interferon [IFN]-β1a) in a phase II trial and two phase III trials regarding clinical and MRI outcomes. Nevertheless, the exact mode of action is still unknown. Alemtuzumab is commonly associated with secondary autoimmune disorders significantly affecting the risk-benefit ratio. Therefore, new biomarkers predicting treatment response and adverse events are urgently needed. This study aims to further elucidate the mechanism of action of the neuroprotective potential of alemtuzumab in relapsing-remitting multiple sclerosis (RRMS). Methods/Design This is a 3-year multicentre, explorative study including overall 150 patients comprising three different groups: (i) de novo patients prior and after alemtuzumab treatment initiation, (ii) patients under alemtuzumab treatment and (iii) patients requiring more than two alemtuzumab infusions. Peripheral blood and serum samples will be collected semi-annually for several in vitro/ex vivo assays to detect and characterize immune cells including their functional activity. Furthermore, data of MRI scans and disease-related impairment (using EDSS and MSFC), as well as the number and time of relapses, will be assessed. The clinical study is registered at clinicaltrials.gov (NCT04082260). Perspective Our study will provide deep insights into the underlying immunological changes in a longitudinal analysis of alemtuzumab treated RRMS patients. By combining clinical, radiological and functional immune-phenotype data, we will be able to identify biomarkers and/or immune signatures predicting treatment response and adverse events. Thereby, the understanding of the mechanisms of action of alemtuzumab will improve its efficacy and safety for present and future patients.

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

2015 ◽  
Vol 6 (5) ◽  
pp. e1741-e1741 ◽  
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.

scholarly journals Altered peripheral blood Th17 and follicular T-helper subsets in patients with pulmonary tuberculosis

2019 ◽  
Vol 9 (2) ◽  
pp. 304-314
Author(s):  
I. V. Kudryavtsev ◽  
M. K Serebriakova ◽  
A. A. Starshinova ◽  
Yu. S. Zinchenko ◽  
N. Yu. Basantsova ◽  
...  
Keyword(s):  
T Cell ◽  
Peripheral Blood ◽  
Central Memory ◽  
T Cell Subsets ◽  
Th2 Cells ◽  
Effector Memory ◽  
Control Group ◽  
T Helper ◽  
Th Cells ◽  
Tfh Cells

Tuberculosis (TB) is one of the most common infections worldwide. Eradication of an intracellular pathogen M. tuberculosis requires to induce a Th1 response by activating IFNγ-producing tissue macrophages. Along with Th1 cells, various subsets of Th17 and follicular T-helper cells (Tfh) able to secrete a broad range of cytokines, including IFNγ, can also be involved in eliminating bacterial pathogens. It justified analyzing in this study changes in percentage of various peripheral blood Th subsets, including Th1, Th2, Th17 and Tfh cells, in TB patients. For this, major CD3+CD4+T cell subsets were assessed by using multicolor flow cytometry in TB patients (n = 40) and healthy volunteers (n = 30). It was found that in TB patients vs. control group percentage of peripheral blood CD45RA–CCR7+ central memory (CM) Th was decreased also affecting frequency of some functional T cell subsets, e.g. either lowering Th2 cells (9.11% (6.95; 13.77) vs. 7.21% (5.64; 9.84), p = 0.012) or elevating CCR6+ Th17 subsets (35.92% (27.72; 41.06) vs. 40.39% (35.41; 47.79; p = 0.016), respectively, but not influencing Th1 and Tfh subsets frequencies. Moreover, percentage of total CCR6+CM Th cells in TB patients vs. control was decreased in CCR4–CXCR3+Th17.1 cell subset (42.87% (33.64; 49.45) vs. 52.26% (46.45; 56.95), p < 0.001), whereas standard CCR4+CXCR3–Th17 and CCR6+ DP Th17 subsets were elevated (p = 0.005 and p = 0.002, respectively). In addition, altered Tfh subset composition associated with the increased (p = 0.021) percentage of CXCR3–CCR6–Tfh2 cells, but decreased CXCR3+CCR6–Tfh1 cells (p = 0.036) was observed. Finally, frequency of peripheral blood Th subsets noted above was also analyzed within effector memory (CD45RA–CCR7–) cells. It was found that in TB patients vs. volunteers frequency of Th17.1 cells was also significantly lower (p = 0.006) in CCR6+EM Th (54.43% (41.19; 91.92) vs. 61.76% (54.01; 65.63), whereas percentage of double-positive Th17 was significantly increased (20.83% (15.12; 30.87) and 12.93 % (9.80; 19.01), respectively, p < 0.001). Thus, it suggests that during M. tuberculosis infection percentage of IFNγ-producing Th17 and Tfh cells was reduced compared to control group also affecting both central memory Th cells patrolling peripheral lymphoid organs as well as effector memory Th cells able to exit to site of infection. 

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