scholarly journals Leukocyte Counts and T Cell Frequencies Differ Between Novel Subgroups of Diabetes and Associate with Metabolic Parameters and Biomarkers of Inflammation

2021 ◽  
Author(s):  
Jacqueline M. Ratter-Rieck ◽  
Haifa Maalmi ◽  
Sandra Trenkamp ◽  
Oana-Patricia Zaharia ◽  
Wolfgang Rathmann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Cell ◽  
Autoimmune Diabetes ◽  
Cell Types ◽  
Recent Onset ◽  
Insulin Resistant ◽  
Cell Counts ◽  
Age Related

Frequencies of circulating immune cells are altered in type 1 and type 2 diabetes compared with healthy individuals and associate with insulin sensitivity, glycemic control and lipid levels. This study aimed to determine whether specific immune cell types are associated with novel diabetes subgroups. We analyzed automated white blood cell counts (n=669) and flow cytometry data (n=201) of participants of the German Diabetes Study with recent-onset (<1 year) diabetes, who were allocated to five subgroups based on data-driven analysis of clinical variables. Leukocyte numbers were highest in severe insulin-resistant diabetes (SIRD) and moderate obesity-related diabetes (MOD) and lowest in severe autoimmune diabetes (SAID). CD4<sup>+</sup> T cell frequencies were higher in SIRD vs. SAID, MOD and mild age-related diabetes (MARD), and frequencies of CCR4<sup>+</sup> regulatory T cells were higher in SIRD vs. SAID and MOD and MARD vs. SAID. Pairwise differences between subgroups were partially explained by differences in clustering variables. Frequencies of CD4<sup>+</sup> T cells were positively associated with age, BMI, HOMA2-B and HOMA2-IR, and frequencies of CCR4<sup>+</sup> regulatory T cells with age, HOMA2-B and HOMA2-IR. In conclusion, different leukocyte profiles exist between novel diabetes subgroups and suggest distinct inflammatory processes in these diabetes subgroups.

scholarly journals Leukocyte Counts and T Cell Frequencies Differ Between Novel Subgroups of Diabetes and Associate with Metabolic Parameters and Biomarkers of Inflammation

2021 ◽  
Author(s):  
Jacqueline M. Ratter-Rieck ◽  
Haifa Maalmi ◽  
Sandra Trenkamp ◽  
Oana-Patricia Zaharia ◽  
Wolfgang Rathmann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Cell ◽  
Autoimmune Diabetes ◽  
Cell Types ◽  
Recent Onset ◽  
Insulin Resistant ◽  
Cell Counts ◽  
Age Related

Frequencies of circulating immune cells are altered in type 1 and type 2 diabetes compared with healthy individuals and associate with insulin sensitivity, glycemic control and lipid levels. This study aimed to determine whether specific immune cell types are associated with novel diabetes subgroups. We analyzed automated white blood cell counts (n=669) and flow cytometry data (n=201) of participants of the German Diabetes Study with recent-onset (<1 year) diabetes, who were allocated to five subgroups based on data-driven analysis of clinical variables. Leukocyte numbers were highest in severe insulin-resistant diabetes (SIRD) and moderate obesity-related diabetes (MOD) and lowest in severe autoimmune diabetes (SAID). CD4<sup>+</sup> T cell frequencies were higher in SIRD vs. SAID, MOD and mild age-related diabetes (MARD), and frequencies of CCR4<sup>+</sup> regulatory T cells were higher in SIRD vs. SAID and MOD and MARD vs. SAID. Pairwise differences between subgroups were partially explained by differences in clustering variables. Frequencies of CD4<sup>+</sup> T cells were positively associated with age, BMI, HOMA2-B and HOMA2-IR, and frequencies of CCR4<sup>+</sup> regulatory T cells with age, HOMA2-B and HOMA2-IR. In conclusion, different leukocyte profiles exist between novel diabetes subgroups and suggest distinct inflammatory processes in these diabetes subgroups.

Suppressive activity of regulatory T cells correlates with high CD4+ T-cell counts and low T-cell activation during chronic simian immunodeficiency virus infection

AIDS ◽  
2011 ◽  
Vol 25 (5) ◽  
pp. 585-593 ◽  
Author(s):  
Ingrid Karlsson ◽  
Benoît Malleret ◽  
Patricia Brochard ◽  
Benoît Delache ◽  
Julien Calvo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Infection ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Suppressive Activity ◽  
Cell Counts ◽  
Immunodeficiency Virus

scholarly journals T cell subset-selective IL2RA enhancers shape autoimmune diabetes risk

2020 ◽  
Author(s):  
Dimitre R. Simeonov ◽  
Harikesh S. Wong ◽  
Jessica T. Cortez ◽  
Arabella Young ◽  
Zhongmei Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Regulatory T Cells ◽  
Disease Progression ◽  
Genetic Variants ◽  
Immune Cell ◽  
Disease Risk ◽  
Autoimmune Diabetes ◽  
Cell Subset ◽  
Regulatory Elements

The majority of genetic variants associated with complex human autoimmune diseases reside in enhancers1–3, non-coding regulatory elements that control gene expression. In contrast with variants that directly alter protein-coding sequences, enhancer variants are predicted to tune gene expression modestly and function in specific cellular contexts4, suggesting that small alterations in the functions of key immune cell populations are sufficient to shape disease risk. Here we tested this concept by experimentally perturbing distinct enhancers governing the high affinity IL-2 receptor alpha chain (IL2RA; also known as CD25). IL2RA is an immune regulator that promotes the pro- and anti-inflammatory functions of conventional T cells (Tconvs) and regulatory T cells (Tregs), respectively, and non-coding genetic variants in IL2RA have been linked to multiple autoimmune disorders4. We previously tiled across the IL2RA locus using CRISPR-activation and identified a stimulation-responsive element (CaRE4) with an enhancer that modestly affects the kinetics of IL2RA expression in Tconvs5. This enhancer is conserved across species and harbors a common human SNP associated with protection from Type 1 Diabetes (T1D)5,6. We now identified an additional conserved enhancer, termed CaRE3 enhancer, which modestly affected steady state IL2RA expression in regulatory T cells (Tregs). Despite their seemingly subtle impact on gene expression, the CaRE3 and CaRE4 enhancers had pronounced yet divergent effects on the incidence of diabetes in autoimmune prone animals. Deletion of the conserved CaRE4 enhancer completely protected against autoimmune diabetes even in animals treated with an immunostimulating anti-PD1 checkpoint inhibitor, whereas deletion of the CaRE3 enhancer accelerated spontaneous disease progression. Quantitative multiplexed imaging of the pancreatic lymph nodes (panLNs) revealed that each enhancer deletion preferentially affected the protein expression levels of IL2RA in activated Tconvs or Tregs, reciprocally tuning local competition for IL-2 input signals. In animals lacking the CaRE4 enhancer, skewed IL-2 signaling favored Tregs, increasing their local density around activated Tconvs to strongly suppress emergence of autoimmune effectors. By contrast, in animals lacking the CaRE3 enhancer, IL-2 signals were skewed towards activated Tconvs, promoting their escape from Treg control. Collectively, this work illustrates how subtle changes in gene regulation due to non-coding variation can significantly alter disease progression and how distinct enhancers controlling the same gene can have opposing effects on disease outcomes through cell type-selective activity.

scholarly journals Trajectories of inflammatory biomarkers over the eighth decade and their associations with immune cell counts and epigenetic ageing

2018 ◽  
Author(s):  
Anna J Stevenson ◽  
Daniel L McCartney ◽  
Sarah E Harris ◽  
Adele M Taylor ◽  
Paul Redmond ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
High Sensitivity ◽  
Inflammatory Biomarkers ◽  
Cell Counts ◽  
Age Related ◽  
Epigenetic Age ◽  
Epigenetic Age Acceleration ◽  
Low Sensitivity

ABSTRACTBACKGROUNDEpigenetic age acceleration (an older methylation age compared to chronological age) correlates strongly with various age-related morbidities and mortality. Chronic systemic inflammation is thought to be a hallmark of ageing but the relationship between an increased epigenetic age and this likely key phenotype of ageing has not yet been extensively investigated.METHODSWe modelled the trajectories of the inflammatory biomarkers C-reactive protein (CRP; measured using both a high- and low-sensitivity assay), and interleukin-6 (IL-6) over the 8th decade in the Lothian Birth Cohort 1936. We additionally investigated the association between CRP and imputed leukocyte counts. Using linear mixed models we examined the cross-sectional and longitudinal association between the inflammatory biomarkers and two measures of epigenetic age acceleration, derived from the Horvath and Hannum epigenetic clocks.RESULTSLow-sensitivity CRP declined, high-sensitivity CRP did not change, and IL-6 increased over time. CRP levels inversely associated with total counts of CD8+T cells and CD4+T cells, and positively associated with senescent CD8+T cells, plasmablasts and granulocytes. Cross-sectionally, the Hannum, but not the Horvath, measure of age acceleration was positively associated with low-sensitivity CRP, high-sensitivity CRP, IL-6 and a restricted measure of CRP (≤10mg/L) likely reflecting levels relevant to chronic inflammation.CONCLUSIONSWe found a divergent relationship between inflammation and immune system parameters in older age. We additionally report the Hannum measure of epigenetic age acceleration associated with an elevated inflammatory profile cross-sectionally, but not longitudinally.

scholarly journals Single-Cell Sequencing of Mouse Heart Immune Infiltrate in Pressure Overload–Driven Heart Failure Reveals Extent of Immune Activation

Circulation ◽  
2019 ◽  
Vol 140 (25) ◽  
pp. 2089-2107 ◽  
Author(s):  
Elisa Martini ◽  
Paolo Kunderfranco ◽  
Clelia Peano ◽  
Pierluigi Carullo ◽  
Marco Cremonesi ◽  
...  
Keyword(s):  
Heart Failure ◽  
T Cells ◽  
Mast Cells ◽  
Natural Killer Cells ◽  
Regulatory T Cells ◽  
Natural Killer ◽  
Immune Activation ◽  
Immune Cell ◽  
Pressure Overload ◽  
Cell Types

Background: Inflammation is a key component of cardiac disease, with macrophages and T lymphocytes mediating essential roles in the progression to heart failure. Nonetheless, little insight exists on other immune subsets involved in the cardiotoxic response. Methods: Here, we used single-cell RNA sequencing to map the cardiac immune composition in the standard murine nonischemic, pressure-overload heart failure model. By focusing our analysis on CD45 + cells, we obtained a higher resolution identification of the immune cell subsets in the heart, at early and late stages of disease and in controls. We then integrated our findings using multiparameter flow cytometry, immunohistochemistry, and tissue clarification immunofluorescence in mouse and human. Results: We found that most major immune cell subpopulations, including macrophages, B cells, T cells and regulatory T cells, dendritic cells, Natural Killer cells, neutrophils, and mast cells are present in both healthy and diseased hearts. Most cell subsets are found within the myocardium, whereas mast cells are found also in the epicardium. Upon induction of pressure overload, immune activation occurs across the entire range of immune cell types. Activation led to upregulation of key subset-specific molecules, such as oncostatin M in proinflammatory macrophages and PD-1 in regulatory T cells, that may help explain clinical findings such as the refractivity of patients with heart failure to anti–tumor necrosis factor therapy and cardiac toxicity during anti–PD-1 cancer immunotherapy, respectively. Conclusions: Despite the absence of infectious agents or an autoimmune trigger, induction of disease leads to immune activation that involves far more cell types than previously thought, including neutrophils, B cells, Natural Killer cells, and mast cells. This opens up the field of cardioimmunology to further investigation by using toolkits that have already been developed to study the aforementioned immune subsets. The subset-specific molecules that mediate their activation may thus become useful targets for the diagnostics or therapy of heart failure.

Immunosuppressive milieu of high-risk localized prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 344-344
Author(s):  
Victor Ricardo Adorno Febles ◽  
Dennis Adeegbe ◽  
Aarif Ahsan ◽  
Jiansheng Wu ◽  
Alireza Khodadad-Jamayran ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Regulatory T Cells ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Immune Cell ◽  
Histological Grade ◽  
Statistical Significance ◽  
Cell Types ◽  
Localized Prostate Cancer

344 Background: The immune factors that modulate the aggressiveness of localized treatment-naïve prostate cancer remain poorly understood. Methods: Fresh tumor and peripheral blood were collected at the time of radical prostatectomy in patients with localized prostate cancer. We evaluated the immune cell composition of 22 patient samples employing multi-parametric flow cytometry. Samples were grouped by histological grade into intermediate (INTPCA) and high-grade (HIGHPCA) prostate cancers based on standard NCCN criteria and immune cell abundances were quantified by mean +/- SEM. Statistical significance was assessed using the Mann-Whitney test. Results: INTPCA and HIGHPCA tumors harbored a similar increase in CD8+ T cells ( p < 0.0005 and p < 0.05, respectively) and CD11b+CD68-CD16+ myeloid-derived cells (p < 0.05) relative to the peripheral blood. Other cell types were similarly decreased in both INTPCA and HIGHPCA, including CD11b+CD68+CD14+ ( p < 0.005 and p < 0.05, respectively). By contrast, regulatory T cells were the only cell type in our analysis to be uniquely enriched in HIGHPCA rather than INTPCA ( p < 0.05). The most unique feature found in phenotypic profiling of the immune repertoire of HIGHPCA relative to INTPCA was an increase in the immune inhibitory receptor ligand, PD-L1, in the tumor associated macrophages (CD11b+CD68+CD14+) compared to the periphery (p < 0.05). Conclusions: Collectively, our findings reveal that HIGHPCA harbors a distinct immunological landscape. Although effector CD8+ T cells are preferentially expressed in the tumor, these are met with an increased proportion of regulatory T cells as well as PD-L1 expressing macrophages that contribute to the inert tumor microenvironment. These are key features of aggressive prostate cancer that may serve as potential biomarkers and therapeutic targets.

scholarly journals Analysis of Regulatory T-cells-specific mRNAs for Improving Prognosis, Immunotherapy Response and Therapeutic Resistance of Patients With Prostate Cancer

2021 ◽  
Author(s):  
Mingyi Ju ◽  
Jingyi Fan ◽  
Yuanjiang Zou ◽  
Mingjie Yu ◽  
Longyang Jiang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Regulatory T Cells ◽  
Cancer Patients ◽  
Tumor Immunity ◽  
Immune Cell ◽  
Cell Types ◽  
Therapeutic Resistance ◽  
Prognostic Signature ◽  
Specific Mrnas

Abstract Background: Prostate cancer recognized as a “cold” tumor has an immunosuppressive microenvironment in which regulatory T-cells (Tregs) usually represent a major role. Therefore, identifying a prognostic signature of Tregs has promising benefits of improving survival of prostate cancer patients. However, the prognostic signature based on Tregs-specific mRNAs for prostate cancer is lacking. Methods: We systematicly analyzed transcriptional profiles of Tregs and 19 other immune cell types using 42 purified immune cell datasets from GEO to identify Tregs-specific mRNAs, and develop and validate a prognostic signature of Tregs (named “TILTregSig”) for monitoring prognosis of prostate cancer using TCGA and ICGC datasets. We also applied the signature to five immunotherapy response datasets and GSCALite to analyze the potential of the TILTregSig for predicting CIT response and cancer therapeutic resistance.Results: We develop the TILTregSig comprising five mRNAs (SOCS2, EGR1, RRM2, TPP1 and C11orf54) for prostate cancer patients. We find that the TILTregSig is a stronger predictor for tumor immunity compared with tumor mutation burden (TMB) and glycolytic activity which have been reported as immune predictors. Further analyses indicate that the TILTregSig may influence tumor immunity mainly by mediating tumor-infiltrating Tregs. Moreover, the TILTregSig also shows promising potential for predicting cancer immunotherapy (CIT) response and therapeutic resistance in multiple cancers.Conclusions: Our study has highlighted the value of the TILTregSig as a prognostic biomarker of prostate cancer from a tumor-infiltrating Tregs perspective, and strengthened its potential application as predictor of CIT response and cancer therapeutic resistance, which warrants further.

scholarly journals Differences in Biomarkers of Inflammation Between Novel Subgroups of Recent-Onset Diabetes

2021 ◽  
Author(s):  
Christian Herder ◽  
Haifa Maalmi ◽  
Klaus Strassburger ◽  
Oana-Patricia Zaharia ◽  
Jacqueline M. Ratter ◽  
...  
Keyword(s):  
Autoimmune Diabetes ◽  
Serum Levels ◽  
Recent Onset ◽  
Insulin Resistant ◽  
Onset Diabetes ◽  
Age Related ◽  
Multiple Biomarkers ◽  
Adult Onset Diabetes ◽  
Clustering Approach ◽  
Mild Obesity

A novel clustering approach identified five subgroups of diabetes with distinct progression trajectories of complications. We hypothesized that these subgroups differ in multiple biomarkers of inflammation. Serum levels of 74 biomarkers of inflammation were measured in 414 individuals with recent adult-onset diabetes from the German Diabetes Study (GDS) allocated to five subgroups based on data-driven analysis. Pairwise differences between subgroups for biomarkers were assessed with generalized linear mixed models before (model 1) and after adjustment (model 2) for the clustering variables. Participants were assigned to five subgroups: severe autoimmune diabetes (SAID, 21%), severe insulin-deficient diabetes (SIDD, 3%), severe insulin-resistant diabetes (SIRD, 9%), mild obesity-related diabetes (MOD, 32%) and mild age-related diabetes (MARD, 35%). In model 1, 23 biomarkers showed ≥1 pairwise difference between subgroups (Bonferroni-corrected p<0.0007). Biomarker levels were generally highest in SIRD and lowest in SIDD. All 23 biomarkers correlated with ≥1 of the clustering variables. In model 2, three biomarkers (CASP-8, EN-RAGE, IL-6) showed at least one pairwise difference between subgroups (e.g. lower CASP8, EN-RAGE and IL-6 in SIDD vs. all other subgroups, all p<0.0007). Thus, novel diabetes subgroups show multiple differences in biomarkers of inflammation, underlining a prominent role of inflammatory pathways in particular in SIRD.

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