scholarly journals FoxP3− Tr1 Cell in Generalized Myasthenia Gravis and Its Relationship With the Anti-AChR Antibody and Immunomodulatory Cytokines

2021 ◽  
Vol 12 ◽  
Author(s):  
Huanyu Meng ◽  
Shuyu Zheng ◽  
Qinming Zhou ◽  
Yining Gao ◽  
You Ni ◽  
...  
Keyword(s):  
T Cell ◽  
Myasthenia Gravis ◽  
Treg Cells ◽  
Pathophysiological Mechanism ◽  
Cell Ratio ◽  
Positive Correlation ◽  
And Function ◽  
The Relationship ◽  
Normal Controls ◽  
Tr1 Cells

Introduction: The changes in the number and function of regulatory T cells (Tregs) are thought to play important roles in the pathogenesis of generalized myasthenia gravis (gMG). Previous studies have suggested the decrease of FoxP3+ Treg cells in the MG development. However, there is no study on the pathophysiological mechanism of FoxP3−Treg, especially Tr1 cells, in gMG patients. Therefore, this study was conducted to reveal the effect of Tr1 cells to the pathophysiology of gMG.Methods: Thirteen patients with gMG and twelve healthy volunteers were enrolled in this study. The titer of anti-AChR Ab was measured by ELISA. The separated PBMCs were labeled for CD4, CD25, CD49b, LAG3 and FoxP3. The CD4+ T cell count, FoxP3+ Treg to CD4+ T cell ratio and Tr1 cell to CD4+ T cell ratio were measured by flow cytometry. Based on the FoxP3+ Treg and Tr1 cell to CD4+ T cell ratios, the patients' Tr1 cell to FoxP3+ Treg ratios were calculated. The IL-6, IL-7, IL-10, TGF-β and IFN-γ concentration in the serum of MG patients and normal controls (NCs) were measured via ELISA.Results: We found a significantly positive correlation between the Tr1 cell/CD4+ T cell ratio and the anti-AChR Ab (r = 0.6889 ± 0.4414, p = 0.0401). Although there were no significant differences in the relationship between FoxP3+ Treg cells and anti-AChR Ab, a positive correlation between the Tr1 cell/FoxP3+ Treg cell ratio and the anti-AChR Ab (r = 0.7110 ± 0.4227, p = 0.0318) was observed. In addition, the Tr1 cell/CD4+ T cell ratio but not the proportion of FoxP3+ Tregs was positively correlated with IL-10 (p = 0.048). These results suggested that in the process of the immunomodulatory effect of Tr1 cells in patients with gMG, IL-10 and other cytokines may be involved, but the specific mechanism needs further study.Conclusion: This is the first study of the immunoregulatory mechanism of Tr1 cells in gMG. We conducted this study to elucidate the significance of Tr1 cells in the pathogenesis of MG. We believe that in patients with gMG, Tr1 cells may play an immunomodulatory role in counteracting AChR-related autoimmune responses. In this process, IL-10 and other immunomodulatory cytokines may be involved.

scholarly journals Efficient IL-2R signaling differentially affects the stability, function, and composition of the regulatory T-cell pool

2021 ◽  
Author(s):  
Marc Permanyer ◽  
Berislav Bošnjak ◽  
Silke Glage ◽  
Michaela Friedrichsen ◽  
Stefan Floess ◽  
...  
Keyword(s):  
T Cell ◽  
Treg Cell ◽  
Cell Function ◽  
Interleukin 2 ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Receptor Expression ◽  
Spontaneous Mutant ◽  
Cell Pool ◽  
And Function

AbstractSignaling via interleukin-2 receptor (IL-2R) is a requisite for regulatory T (Treg) cell identity and function. However, it is not completely understood to what degree IL-2R signaling is required for Treg cell homeostasis, lineage stability and function in both resting and inflammatory conditions. Here, we characterized a spontaneous mutant mouse strain endowed with a hypomorphic Tyr129His variant of CD25, the α-chain of IL-2R, which resulted in diminished receptor expression and reduced IL-2R signaling. Under noninflammatory conditions, Cd25Y129H mice harbored substantially lower numbers of peripheral Treg cells with stable Foxp3 expression that prevented the development of spontaneous autoimmune disease. In contrast, Cd25Y129H Treg cells failed to efficiently induce immune suppression and lost lineage commitment in a T-cell transfer colitis model, indicating that unimpaired IL-2R signaling is critical for Treg cell function in inflammatory environments. Moreover, single-cell RNA sequencing of Treg cells revealed that impaired IL-2R signaling profoundly affected the balance of central and effector Treg cell subsets. Thus, partial loss of IL-2R signaling differentially interferes with the maintenance, heterogeneity, and suppressive function of the Treg cell pool.

CD4+ Foxp3+ regulatory T cell-mediated immunomodulation by anti-depressants inhibiting acid sphingomyelinase

2018 ◽  
Vol 399 (10) ◽  
pp. 1175-1182 ◽  
Author(s):  
Jürgen Schneider-Schaulies ◽  
Niklas Beyersdorf
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treg Cells ◽  
Tricyclic Antidepressant ◽  
Acid Sphingomyelinase ◽  
Human T Cells ◽  
And Function ◽  
Rate Limiting ◽  
Deficient Mice

AbstractAcid sphingomyelinase (ASM) is the rate-limiting enzyme cleaving sphingomyelin into ceramide and phosphorylcholin. CD4+Foxp3+regulatory T (Treg) cells depend on CD28 signaling for their survival and function, a receptor that activates the ASM. Both, basal and CD28-induced ASM activities are higher in Treg cells than in conventional CD4+T (Tconv) cells. In ASM-deficient (Smpd1−/−) as compared to wt mice, membranes of T cells contain 7–10-fold more sphingomyelin and two- to three-fold more ceramide, and are in a state of higher order than membranes of T cells from wt mice, which may facilitate their activation. Indeed, the frequency of Treg cells among CD4+T cells in ASM-deficient mice and their suppressive activityin vitroare increased. Moreover,in vitrostimulation of ASM-deficient T cells in the presence of TGF-β and IL-2 leads to higher numbers of induced Treg cells. Pharmacological inhibition of the ASM with a clinically used tricyclic antidepressant such as amitriptyline in mice or in tissue culture of murine or human T cells induces higher frequencies of Treg cells among CD4+T cells within a few days. This fast alteration of the balance between T cell populationsin vitrois due to the elevated cell death of Tconv cells and protection of the CD25highTreg cells by IL-2. Together, these findings suggest that ASM-inhibiting antidepressants, including a fraction of the serotonin re-uptake inhibitors (SSRIs), are moderately immunosuppressive and should be considered for the therapy of inflammatory and autoimmune disorders.

T Regulatory Cell Activation Exists in Pathogenesis of Polycythaemia Vera.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4642-4642
Author(s):  
Xin Wang ◽  
Wenbo Zhao ◽  
Yanxia Liu ◽  
Ying Li
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Protein Level ◽  
Treg Cells ◽  
T Cell Immunity ◽  
Polycythaemia Vera ◽  
Cell Immunity ◽  
And Function ◽  
Hematopoietic Activity

Abstract Polycythaemia vera (PV) is a clonal disorder arising from a pluripotent hematopoietic progenitor cell. The etiology of PV remains unknown and there is no consensus as to the optimal therapy for this disorder. T regulatory (Treg) cells play a vital role in the maintenance of self-tolerance, control of auto-immunity and regulation of T-cell homeostasis, and they modulate overall immune responses against a variety of pathogens. Recent studies revealed that Treg cells play a crucial role in the process of hematopoietic activity. However, the effect of Treg cells in PV has not been reported. The Treg cells might participate in the dysfunction of T-cell immunity in PV. The profile and function of Treg cells in PV patients were explored in this study. Peripheral blood was withdrawn from 21 PV patients (Female 8 ; Male 13), as well as 25 age-matched healthy donors (F 9 ; M 16) as controls. All samples were taken after informed consent and collected from PV patients prior to treatment. Diagnoses of PV were made according to clinical and laboratory criteria. The peripheral blood mononuclear cells (PBMCs) were subjected to flow cytometry analyses after labeling with anti-CD4, anti-CD25, and anti-Foxp3 antibodies. Real-time PCR and Western blotting were also performed to identify quantitative FOXP3 mRNA expression and protein level in the PBMCs from PV in comparison to controls. The relationships between the percentage of Treg cells, the expressions for quantitative mRNA and protein, with the clinical data were assessed. The percentage of CD4+ T-cells was significant decreased in the group of PV than in normal control (28.7±7.07% vs 38.6±8.38%, p<0.05). But the percentage of CD4+CD25+FOXP3+ T-cells (Treg cells) in PV patients was significantly increased when compared to the control (10.93±4.02% vs 5.86±1.99%, p<0.05). Moreover, the quantitative mRNA expression of FOXP3 (64.23±18.52 vs 16.06±4.78, p<0.05) and protein expression of FOXP3 (0.74±0.16 vs 0.62±0.10, p<0.05)) were significantly enhanced in PV patients (shown in Figure 1). In conclusion, we showed that patients with PV have enhanced percentage of Treg cells in their peripheral blood. This was substantiated further with the finding that overexpressions of FOXP3 in PV both in mRNA and protein level. These results highlight important Treg-cell abnormalities in patients with PV because natural Treg cells are significantly increased in number and function. The underlying mechanism is still undefined, but the increased frequency and function of Treg cells might account for the abnormal T cell immunity in PV patients. It was suggested that there may be differently suppressive machanisms for Treg in these patients. The elevated Treg cells in PV might be activated and then affect the hematopoietic activity. We believe that Treg cells might involved in the dysfunction of T/NK cells in their disability to downregulate the hematopoietic proliferation in PV. And the expansion of Treg cells may be a feature of PV and associated with the pathogenesis of PV. Further investigation in this abnormality might provide novel therapy clue for this disease. Figure Figure

scholarly journals Delusional thinking and action binding in healthy individuals

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Liyu Cao ◽  
Michael B. Steinborn ◽  
Barbara F. Haendel
Keyword(s):  
Continuous Distribution ◽  
Positive Symptoms ◽  
Healthy Individuals ◽  
Positive Correlation ◽  
Binding Effect ◽  
Testing Method ◽  
Action Time ◽  
Timing Measurement ◽  
The Relationship ◽  
Normal Controls

AbstractAction binding is the effect that the perceived time of an action is shifted towards the action related feedback. A much larger action binding effect in schizophrenia compared to normal controls has been shown, which might be due to positive symptoms like delusions. Here we investigated the relationship between delusional thinking and action binding in healthy individuals, predicting a positive correlation between them. The action binding effect was evaluated by comparing the perceived time of a keypress between an operant (keypress triggering a sound) and a baseline condition (keypress alone), with a novel testing method that massively improved the precision of the subjective timing measurement. A positive correlation was found between the tendency of delusional thinking (measured by the 21-item Peters et al. delusions inventory) and action binding across participants after controlling for the effect of testing order between operant and baseline conditions. The results indicate that delusional thinking in particular influences action time perception and support the notion of a continuous distribution of schizotypal traits with normal controls at one end and clinical patients at the other end.

scholarly journals The Role of PDE8 in T Cell Recruitment and Function in Inflammation

2021 ◽  
Vol 9 ◽  
Author(s):  
Paul M. Epstein ◽  
Chaitali Basole ◽  
Stefan Brocke
Keyword(s):  
Cell Adhesion ◽  
T Cell ◽  
Cell Motility ◽  
Treg Cells ◽  
Chronic Obstructive ◽  
Kinase Signaling ◽  
Cns Inflammation ◽  
Obstructive Pulmonary Disease ◽  
Signaling Complex ◽  
And Function

Inhibitors targeting cyclic nucleotide phosphodiesterases (PDEs) expressed in leukocytes have entered clinical practice to treat inflammatory disorders, with three PDE4 inhibitors currently in clinical use as therapeutics for psoriasis, psoriatic arthritis, atopic dermatitis and chronic obstructive pulmonary disease. In contrast, the PDE8 family that is upregulated in pro-inflammatory T cells is a largely unexplored therapeutic target. It was shown that PDE8A plays a major role in controlling T cell and breast cancer cell motility, including adhesion to endothelial cells under physiological shear stress and chemotaxis. This is a unique function of PDE8 not shared by PDE4, another cAMP specific PDE, employed, as noted, as an anti-inflammatory therapeutic. Additionally, a regulatory role was shown for the PDE8A-rapidly accelerated fibrosarcoma (Raf)-1 kinase signaling complex in myelin antigen reactive CD4+ effector T cell adhesion and locomotion by a mechanism differing from that of PDE4. The PDE8A-Raf-1 kinase signaling complex affects T cell motility, at least in part, via regulating the LFA-1 integrin mediated adhesion to ICAM-1. The findings that PDE8A and its isoforms are expressed at higher levels in naive and myelin oligodendrocyte glycoprotein (MOG)35–55 activated effector T (Teff) cells compared to regulatory T (Treg) cells and that PDE8 inhibition specifically affects MOG35–55 activated Teff cell adhesion, indicates that PDE8A could represent a new beneficial target expressed in pathogenic Teff cells in CNS inflammation. The implications of this work for targeting PDE8 in inflammation will be discussed in this review.

FOXP3 Expression in B and T Cell Lymphomas.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4503-4503
Author(s):  
Giovanna Roncador ◽  
Juan Fernando Garcia ◽  
Jose Francisco Garcia ◽  
Lorena Maestre ◽  
Elena Lucas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory Gene ◽  
Immune Surveillance ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Cell Leukaemia ◽  
Tissue Sections ◽  
T Cell Lymphomas ◽  
And Function

Abstract Foxp3, which encodes a forkhead/winged helix transcription factor designated Scurfin, is a key regulatory gene required for the development and function of regulatory CD4+CD25+ T cells (Treg), a subpopulation of T-cells specialized in maintaining the balance between immunity and tolerance. Humans with defects in the FOXP3 gene, develop strong activation of the immune system, leading to multiorgan autoimmune disease, allergies, inflammatory bowel disease and severe infections, collectively known as the IPEX syndrome (immune deregulation, polyendocrinopathy, enteropathy, X-linked inheritance syndrome) Because of the importance of FOXP3 in the development and function of Treg cells, and its potential use as a specific Treg marker, we have developed several monoclonal antibodies against FOXP3, for use on paraffin-embedded tissue sections and evaluated its expression in a large series (150 cases) of B- and T-cell lymphomas. In reactive lymphoid tissue, strong nuclear FOXP3 expression was observed in approximately 5% of interfollicular T-cells. FOXP3 expression in tumour cells was confined to most of Adult T-cell Leukaemia/Lymphoma (ATLL) cases (68%), with some variability in protein expression. In other lymphoma types, FOXP3 expression was only detected in the reactive T-cell background, and the number of FOXP3-positive reactive T-cells was variable, ranging from almost a complete absence (Burkitt’s lymphoma) to abundant infiltrate (common in follicular lymphoma). In conclusion, the availability of a FOXP3 monoclonal antibody, not only provides an important tool for the study of the development and function of Treg cells, but also represents a useful marker for the identification of ATLL cases in formalin-fixed paraffin-embedded tissue sections. The presence or absence of Treg cells in the tumour environment could also play a role in the immune surveillance of tumours, thus implying a potential additional value for the detection of this cell population in tumour samples.

Elevated cerebrospinal fluid CD4+/CD8+ T cell ratio in myasthenia gravis

1990 ◽  
Vol 30 (2-3) ◽  
pp. 219-227 ◽  
Author(s):  
Kiti M.I. Müller ◽  
Eero Taskinen ◽  
Matti Iivanainen
Keyword(s):  
Cerebrospinal Fluid ◽  
T Cell ◽  
Myasthenia Gravis ◽  
Cd8 T Cell ◽  
Cell Ratio

scholarly journals Functional defect of regulatory CD4+CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 735-741 ◽  
Author(s):  
Anna Balandina ◽  
Sandrine Lécart ◽  
Philippe Dartevelle ◽  
Abdelhadi Saoudi ◽  
Sonia Berrih-Aknin
Keyword(s):  
T Cells ◽  
T Cell ◽  
Autoimmune Disease ◽  
Myasthenia Gravis ◽  
Cell Function ◽  
Critical Role ◽  
Treg Cells ◽  
Regulatory Function ◽  
Phenotypic Analysis ◽  
Functional Defect

AbstractThymus-derived CD4+CD25+ regulatory T (Treg) cells are essential for the maintenance of immunologic self-tolerance. Despite their critical role in the active suppression of experimental autoimmune disorders, little is known about their involvement in human autoimmune diseases. Myasthenia gravis (MG) is a CD4+ T cell–dependent autoimmune disease and the thymus is assumed to be the initiation site. To identify possible defects in the Treg cells in MG, we analyzed CD4+CD25+ cells in thymi from patients with MG compared to those from healthy subjects. We found a normal CD4+CD25+ number but a severe functional defect in their regulatory activity together with a decreased expression of the transcription factor, Foxp3, which is essential for T-cell regulatory function. The phenotypic analysis of CD4+CD25+ thymocytes revealed an increased number of activated effector cells with strong Fas expression in patients with MG. However, whatever their level of Fas, CD4+CD25+ thymocytes from patients with MG remained unable to suppress the proliferation of responding cells, indicating that the impaired Treg cell function is not due to contamination by activated effector T cells. These data are the first to demonstrate a severe functional impairment of thymic Treg cells in MG, which could contribute to the onset of this autoimmune disease.

Cold reactive lymphocytotoxic activity in autoimmune thyroid disease

1985 ◽  
Vol 109 (4) ◽  
pp. 492-498 ◽  
Author(s):  
Marilyn Ryan ◽  
Vitaya Sridama ◽  
Leslie J. DeGroot
Keyword(s):  
Monoclonal Antibodies ◽  
T Cell ◽  
B Cells ◽  
Thyroid Disease ◽  
Autoimmune Thyroid Disease ◽  
T Cell Subsets ◽  
Graves Disease ◽  
Positive Correlation ◽  
Autoimmune Thyroid ◽  
Normal Controls

Abstract. An increased incidence of cold-reactive lymphocytotoxic activity (LCTA) has been demonstrated in the sera of patients with autoimmune thyroid disease. Twenty-six of 79 (33%) patients with Graves' disease and 9 of 21(43%) patients with Hashimoto's thyroiditis had cold-reactive LCTA detected by microcytotoxicity assay compared to 6 of 42 (14%) normal controls. There was no correlation between LCTA and age, sex, MCHA titre or TGHA titre. A positive correlation with FTI and LCTA in Hashimoto's patients was demonstrated, but no such correlation was demonstrable in Graves' patients. The lymphocytotoxic activity was directed preferentially against B cells. There was no preferential lysis of T-cell subsets as defined by monoclonal antibodies, and the lymphocytotoxins were equally reactive with normal lymphocytes and toxic Graves' lymphocytes. The significance of cold-reactive lymphocytotoxic activity in the pathogenesis of autoimmune thyroid disease remains to be determined.

scholarly journals Beyond type 1 regulatory T cells: co-expression of LAG3 and CD49b in IL-10-producing T cell lineages

2018 ◽  
Author(s):  
Weishan Huang ◽  
Sabrina Solouki ◽  
Chavez Carter ◽  
Song-Guo Zheng ◽  
Avery August
Keyword(s):  
T Cells ◽  
T Cell ◽  
Treg Cells ◽  
Cell Lineages ◽  
Transgenic Murine Model ◽  
Differentiation Stage ◽  
Tr1 Cells

ABSTRACTType 1 regulatory CD4+T (Tr1) cells express high levels of the immunosuppressive cytokine IL-10 but not the master transcription factor Foxp3, and can suppress inflammation and promote immune tolerance. In order to identify and obtain viable Tr1 cells for research and clinical applications, co-expression of CD49b and LAG3 has been proposed as a unique surface signature for both human and mouse Tr1 cells. However, recent studies have revealed that this pattern of co-expression is dependent on the stimulating conditions and the differentiation stage of the CD4+T cells. Here, using an IL-10GFP/Foxp3RFPdual reporter transgenic murine model, we demonstrate that co-expression of CD49b and LAG3 is not restricted to the Foxp3−Tr1 cells, but is also observed in Foxp3+T regulatory (Treg) cells and CD8+T cells that produce IL-10. Our data indicate that IL-10-producing Tr1 cells, Treg cells and CD8+T cells are all capable of co-expressing LAG3 and CD49bin vitrofollowing differentiation under IL-10-inducing conditions, andin vivofollowing pathogenic insult or infection in the pulmonary mucosa. Our findings urge caution in the use of LAG3/CD49b co-expression to identify Tr1 cells, since it may mark IL-10-producing T cell lineages more broadly, including the Foxp3−Tr1 cells, Foxp3+Treg cells and CD8+T cells.

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