Skewed X chromosomal inactivation impacts T regulatory cell function in systemic sclerosis

2010 ◽  
Vol 69 (12) ◽  
pp. 2213-2216 ◽  
Author(s):  
Jasper C A Broen ◽  
Ingrid L M Wolvers-Tettero ◽  
Lenny Geurts-van Bon ◽  
Madelon C Vonk ◽  
Marieke J H Coenen ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Systemic Sclerosis ◽  
T Regulatory Cells ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Magnetic Bead ◽  
T Regulatory Cell ◽  
Myeloid Dendritic Cells ◽  
Peripheral Blood Mononuclear

ObjectivesTo investigate the role of X chromosomal inactivation (XCI) in systemic sclerosis (SSc) and its effects on forkhead box P3 (Foxp3) expression in T regulatory cells (Tregs).Methods217 women with SSc and 107 healthy women (controls) were included in the study. From these subjects, DNA was isolated from total peripheral blood mononuclear cells, plasmacytoid dendritic cells, T cells, B cells, myeloid dendritic cells and monocytes after magnetic bead separation. All samples were assessed for skewed XCI patterns with the Human Androgen Receptor Assay. The outcome was assessed by linear regression. CD4+CD25+ cells were then isolated and intracellular Foxp3 expression was assessed by flow cytometry.ResultsSkewing was not associated with increased age in patients with SSc, in contrast to the control population (r=0.45, p<0.0001). Taking this into account, a significantly higher frequency of skewed XCI was found in patients with SSc compared with controls (p=0.001). No difference in skewing was observed between the immune cell subsets. In addition, a higher concentration of Foxp3+ cells exhibiting a lower Foxp3 mean fluorescence intensity was found in the patients with SSc, with profound XCI skewing (both p<0.001) associated with less efficient suppressive activity (p=0.012).ConclusionsSkewed XCI plays a role in susceptibility to SSc, is not restricted and influences Foxp3 expression and the suppressive capacity of Tregs.

scholarly journals Longitudinal high-dimensional analysis identifies biomarkers of response to anti-PD-1 immunotherapy

2021 ◽  
Author(s):  
Run-Ze Li ◽  
Xing-Xing Fan ◽  
Ze-Bo Jiang ◽  
Jumin Huang ◽  
Hu-Dan Pan ◽  
...  
Keyword(s):  
Clinical Response ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Response To Therapy ◽  
High Dimensional ◽  
Meso Scale Discovery ◽  
Peripheral Blood Mononuclear ◽  
Poor Outcomes ◽  
Nsclc Patients

Abstract The response to immunotherapy could be better predicted by using a wide set of biomarkers, including serum tumor markers; however, robust immune markers associated with efficacy have yet to be validated. In this study, changes in immune cell subsets from NSCLC patients treated with anti-PD1 therapy were longitudinally monitored by high-dimensional cytometry by time of flight (CyTOF) and Meso Scale Discovery (MSD) multi-cytokines kits. The frequencies of circulating CD8+ and CD8+CD101hiTIM3+ (CCT T) subsets were significantly correlated with clinical response and survival. Enrichment of these populations in peripheral blood mononuclear cells (PBMCs) indicated a poor clinical response to ICB therapy. Cell function assays revealed that these subsets were remarkably impaired, which supported the poor outcomes observed. Additionally, longitudinal analysis showed that KLRG1 expression and cytokines were associated with the response to therapy. Overall, our results provide novel potential biomarkers for guiding the management of NSCLC patients eligible to anti-PD-1 therapy, and contribute insights for new therapeutic strategies.

scholarly journals MicroRNA expression profiling of peripheral blood mononuclear cells associated with syphilis

2019 ◽  
Author(s):  
Tao Huang ◽  
Jun Zhang ◽  
Wujian Ke ◽  
Xiaohui Zhang ◽  
Wentao Chen ◽  
...  
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Treponema Pallidum ◽  
Target Sequence ◽  
Healthy Individuals ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

Abstract Background Treponema pallidum ( T. pallidum ) infection evokes significant immune responses, resulting in tissue damage. The immune mechanism underlying T. pallidum infection is still unclear, although microRNAs (miRNAs) have been shown to influence immune cell function and, consequently, the generation of antibody responses during other microbe infections. However, these mechanisms are unknown for T. pallidum . Methods In this study, we performed a comprehensive analysis of differentially expressed miRNAs in healthy individuals, untreated patients with syphilis, patients in the serofast state, and serologically cured patients. miRNAs were profiled from the peripheral blood of patients obtained at the time of serological diagnosis. Then, both the target sequence analysis of these different miRNAs and pathway analysis were performed to identify important immune and cell signaling pathways. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was performed for microRNA analysis. Results A total of 89 differentially regulated miRNAs were identified. Following RT-qPCR confirmation, three miRNAs (hsa-miR-195-5p, hsa-miR-223-3p, hsa-miR-589-3p) showed significant differences in the serofast and serologically cured states ( P <0.05). One miRNA (hsa-miR-195-5p) showed significant differences between untreated patients and healthy individuals. Conclusions This is the first study of miRNA expression differences in peripheral blood mononuclear cells (PBMCs) in different stages of T. pallium infection. Our study suggests that the combination of three miRNAs has great potential to serve as a non-invasive biomarker of T. pallium infections, which will facilitate better diagnosis and treatment of T. pallium infections.

scholarly journals Interaction of Rotavirus with Human Myeloid Dendritic Cells

2005 ◽  
Vol 79 (23) ◽  
pp. 14526-14535 ◽  
Author(s):  
Carlos F. Narváez ◽  
Juana Angel ◽  
Manuel A. Franco
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Transforming Growth Factor Beta ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Myeloid Dendritic Cells ◽  
Peripheral Blood Mononuclear ◽  
Necrosis Factor Alpha ◽  
Stimulation Of

ABSTRACT We have previously shown that very few rotavirus (RV)-specific T cells that secrete gamma interferon circulate in recently infected and seropositive adults and children. Here, we have studied the interaction of RV with myeloid immature (IDC) and mature dendritic cells (MDC) in vitro. RV did not induce cell death of IDC or MDC and induced maturation of between 12 and 48% of IDC. Nonetheless, RV did not inhibit the maturation of IDC or change the expression of maturation markers on MDC. After treatment with RV, few IDC expressed the nonstructural viral protein NSP4. In contrast, a discrete productive viral infection was shown in MDC of a subset of volunteers, and between 3 and 46% of these cells expressed NSP4. RV-treated IDC secreted interleukin 6 (IL-6) (but not IL-1β, IL-8, IL-10, IL-12, tumor necrosis factor alpha, or transforming growth factor beta), and MDC released IL-6 and small amounts of IL-10 and IL-12p70. The patterns of cytokines secreted by T cells stimulated by staphylococcal enterotoxin B presented by MDC infected with RV or uninfected were comparable. The frequencies and patterns of cytokines secreted by memory RV-specific T cells evidenced after stimulation of peripheral blood mononuclear cells (PBMC) with RV were similar to those evidenced after stimulation of PBMC with RV-infected MDC. Finally, IDC treated with RV strongly stimulated naive allogeneic CD4+ T cells to secrete Th1 cytokines. Thus, although RV does not seem to be a strong maturing stimulus for DC, it promotes their capacity to prime Th1 cells.

scholarly journals Cannabinoid type 2 receptor (CB2R) distribution in dermatomyositis skin and peripheral blood mononuclear cells (PBMCs) and in vivo effects of LenabasumTM

2022 ◽  
Vol 24 (1) ◽  
Author(s):  
Spandana Maddukuri ◽  
Jay Patel ◽  
De Anna Diaz ◽  
Kristen L. Chen ◽  
Maria Wysocka ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mononuclear Cells ◽  
Cytokine Production ◽  
Immune Cell ◽  
Cell Populations ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Ifn Γ

Abstract Background Lenabasum is a cannabinoid type 2 receptor (CB2R) reverse agonist that demonstrates anti-inflammatory effects in vivo and in vitro in dermatomyositis (DM) and is currently being investigated for therapeutic potential. The purpose of our study is to investigate CB2R distribution as well as the effects of lenabasum in DM. Methods Immunohistochemistry staining (IHC) was utilized to examine immune cell and cytokine production changes in lesional DM skin biopsies from lenabasum and placebo-treated patients. CB2R expression in various immune cell populations within DM skin was investigated with image mass cytometry (IMC), whereas flow cytometry elucidated CB2R expression in DM peripheral blood mononuclear cells (PBMCs) as well as cytokine production by CB2R-expressing cell populations. Results After 12 weeks of lenabasum treatment, IHC staining showed that CD4+ T cells, CB2R, IL-31, IFN-γ, and IFN-β cytokines were downregulated. IFN-γ and IFN-β mRNA decreased in lesional DM skin but not in PBMCs. IMC findings revealed that CB2R was upregulated in DM lesional skin compared to HC skin and DM PBMCs (p<0.05). In DM skin, CB2R was upregulated on dendritic cells, B cells, T cells, and macrophages while dendritic cells had the greatest expression in both DM skin and PBMCs (p<0.05). These CB2R+ cells in the skin produce IL-31, IL-4, IFN-γ, and IFN-β. Conclusion Our findings of differential CB2R expression based on location and cell type suggest modes by which lenabasum may exert anti-inflammatory effects in DM and highlights dendritic cells as potential therapeutic targets.

scholarly journals Development of Interleukin-12-Producing Capacity throughout Childhood

2002 ◽  
Vol 70 (12) ◽  
pp. 6583-6588 ◽  
Author(s):  
John W. Upham ◽  
Peter T. Lee ◽  
Barbara J. Holt ◽  
Tricia Heaton ◽  
Susan L. Prescott ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Intrinsic Property ◽  
Interleukin 12 ◽  
Peripheral Blood Mononuclear ◽  
Hla Dr ◽  
Macrophage Colony ◽  
Synthetic Capacity ◽  
Th1 Immune Responses

ABSTRACT Increasing evidence indicates that the capacity to induce protective Th1 immune responses is impaired in early childhood, an observation that can be partially attributed to deficiencies in antigen-presenting-cell function. Synthesis of interleukin 12 (IL-12), a key Th1-trophic cytokine, is markedly reduced in the neonatal period, though there is a paucity of knowledge concerning the ontogeny of IL-12-synthetic capacity throughout the childhood years. Hence, we examined the production of bioactive IL-12 p70 by circulating mononuclear cells in a population of healthy individuals. As expected, the capacity to synthesize IL-12 p70 in response to either lipopolysaccharide or heat-killed Staphylococcus aureus was markedly impaired at birth, even after priming of cells with gamma interferon. Surprisingly however, IL-12 p70 synthesis by peripheral blood mononuclear cells from both 5- and 12-year-old children was still substantially below that seen in adults, and this did not appear to be related to excessive production of IL-10. In contrast, dendritic cells from adults and neonates, derived from monocytes with granulocyte-macrophage colony-stimulating factor and IL-4, synthesized equivalent amounts of IL-12 p70 in response to microbial stimulation. This indicates that the impaired capacity for IL-12 synthesis in childhood is not an intrinsic property of circulating mononuclear cells but rather can be readily overcome in response to appropriate maturational stimuli. Because IL-12 arose predominantly from circulating HLA-DR+ cells that lacked B-cell- and monocyte-specific markers, we propose that the slow maturation of IL-12-synthetic capacity in the childhood years can be attributed to deficiencies in the number and/or function of dendritic cells.

scholarly journals A252 FUNCTIONAL ANALYSIS OF GENETIC AETIOLOGIES IN A DOWNSTREAM OF TYROSINE KINASE (DOK) PROTEIN IN THE PATHOGENESIS OF PEDIATRIC INFLAMMATORY BOWEL DISEASE (IBD)

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. 129-130
Author(s):  
V Batura ◽  
C Guo ◽  
N Warner ◽  
G Leung ◽  
A Ricciuto ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Imaging Techniques ◽  
Inflammatory Disorder ◽  
Zebrafish Model ◽  
Peripheral Blood Mononuclear

Abstract Background IBD is a form of chronic inflammatory disorder of the gastrointestinal tract that arises due to genetic, environmental, immunological and microbial factors. The precise pathological mechanisms remain elusive. It is thought that the onset of pediatric IBD can largely be attributed to genetics. Muise lab, at SickKids, regularly screens children at the SickKids IBD clinic and through an international consortium to find possible genetic links to the disease. We report a patient at SickKids with biallelic mutations in DOK4 who has severe Crohn’s Disease along with other inflammatory conditions. Downstream of kinase (DOK) proteins are a family of adaptor molecules that serve as scaffolding proteins important in regulating cell signaling, especially in T cells. DOK4 has been shown to have negative regulatory effects on T cell activation but is also expressed across various other tissues where its function is yet to be determined. We predict that these mutations are causing immune cell dysregulation, which may be contributing to the patients IBD. Aims Through this study, we aim to enhance our understanding of the pathobiological mechanism of novel mutations in DOK4. Methods We have established T cell lines, expressing wild type and mutated DOK4, which will be used to perform functional tests, such as localization analysis through immunofluorescence and cytokine profiling, to check for T cell function. We have patient derived organoids, which will be used to assess changes in gut morphology using imaging techniques. We will also generate mutant zebrafish model that will be used to determine the susceptibility to colitis related to this mutation, disease progression and gut peristalsis using live imaging technology. Results Preliminary data shows variation in expression of the protein within patient derived peripheral blood mononuclear cells (PBMCs) compared to a healthy donor. Conclusions With this study, we hope to identify new therapeutic targets for patients with DOK4 mutations. Funding Agencies CIHRThe Leona M. and Harry B. Helmsley Charitable Trust

scholarly journals MicroRNA expression profiling of peripheral blood mononuclear cells associated with syphilis

2019 ◽  
Author(s):  
Tao Huang ◽  
Jun Zhang ◽  
Wujian Ke ◽  
Xiaohui Zhang ◽  
Wentao Chen ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Treponema Pallidum ◽  
Target Sequence ◽  
Peripheral Blood Mononuclear ◽  
Non Invasive ◽  
Significant Difference ◽  
Differentially Expressed Mirnas

Abstract Background Treponema pallidum (T. pallidum Tp) infection evokes vigorous immune responses, resulting in tissue damage. The immune mechanism after Treponema pallidum infection is still not clear. MicroRNAs (miRNAs) have been shown, however, to influence immune cell function and consequently the generation of antibody responses during other microbe infections, but these values are unknown for Tp. Methods In this study, we performed a comprehensive analysis of differentially expressed miRNAs in healthy persons, untreated patients with syphilis, patients in the serofast state, and serologically cured patients. MiRNAs were profiled from patient peripheral blood obtained at the time of serological diagnosis. Then both the target sequence analysis on these different miRNAs and pathway analysis were performed to identify important immune and cell signaling pathways. Quantitative RT-PCR for analysis of microRNA Results There were 89 differentially regulated miRNA identified in total. Following RT-qPCR confirmation, three miRNAs (hsa-miR-195-5p, hsa-miR-223-3p, hsa-miR-589-3p) showed significant difference among serofast state, and serological cure (P<0.05). A miRNAs (hsa-miR-195-5p) showed significant differences among untreated patients and healthy individuals. Conclusions This is the first study of miRNA expression difference in PBMCs in different stages of T. pallium infection. Our study suggests that the combination of three miRNAs has great potential to serve as non-invasive biomarkers of Treponema pallidum infections, which will facilitate better diagnosis and treat of T. pallium infections.

scholarly journals MicroRNA expression profiling of peripheral blood mononuclear cells associated with syphilis

2019 ◽  
Author(s):  
Tao Huang ◽  
Jun Zhang ◽  
Wujian Ke ◽  
Xiaohui Zhang ◽  
Wentao Chen ◽  
...  
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Treponema Pallidum ◽  
Target Sequence ◽  
Healthy Individuals ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

Abstract Background Treponema pallidum ( T. pallidum ) infection evokes significant immune responses, resulting in tissue damage. The immune mechanism underlying T. pallidum infection is still unclear, although microRNAs (miRNAs) have been shown to influence immune cell function and, consequently, the generation of antibody responses during other microbe infections. However, these mechanisms are unknown for T. pallidum . Methods In this study, we performed a comprehensive analysis of differentially expressed miRNAs in healthy individuals, untreated patients with syphilis, patients in the serofast state, and serologically cured patients. miRNAs were profiled from the peripheral blood of patients obtained at the time of serological diagnosis. Then, both the target sequence analysis of these different miRNAs and pathway analysis were performed to identify important immune and cell signaling pathways. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was performed for microRNA analysis. Results A total of 89 differentially regulated miRNAs were identified. Following RT-qPCR confirmation, three miRNAs (hsa-miR-195-5p, hsa-miR-223-3p, hsa-miR-589-3p) showed significant differences in the serofast and serologically cured states ( P <0.05). One miRNA (hsa-miR-195-5p) showed significant differences between untreated patients and healthy individuals. Conclusions This is the first study of miRNA expression differences in peripheral blood mononuclear cells (PBMCs) in different stages of T. pallium infection. Our study suggests that the combination of three miRNAs has great potential to serve as a non-invasive biomarker of T. pallium infections, which will facilitate better diagnosis and treatment of T. pallium infections.

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