scholarly journals Common patterns of gene regulation associated with Cesarean section and the development of islet autoimmunity – indications of immune cell activation

2017 ◽  
Author(s):  
M. Laimighofer ◽  
R. Lickert ◽  
R. Fürst ◽  
F. J. Theis ◽  
C. Winkler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 1 Diabetes ◽  
T Lymphocytes ◽  
Cesarean Section ◽  
Cell Activation ◽  
Immune Cell ◽  
Islet Autoimmunity ◽  
Nucleotide Synthesis ◽  
Immune Cell Activation

AbstractBackgroundBirth by Cesarean section increases the risk of developing type 1 diabetes later in life; however, the underlying molecular mechanisms of this effect remain unclear. We aimed to elucidate common regulatory processes observed after Cesarean section and the development of islet autoimmunity, which precedes type 1 diabetes, by investigating the transcriptome of blood cells in the developing immune system.MethodsWe analyzed gene expression of peripheral blood mononuclear cells taken at several time points from children with increased familial and genetic risk for type 1 diabetes (n = 109). We investigated effects of Cesarean section on gene expression profiles of children in the first year of life using a generalized additive mixed model to account for the longitudinal data structure. To investigate the effect of islet autoimmunity, we compared gene expression differences between children after initiation of islet autoimmunity and age-matched children who did not develop islet autoantibodies. Finally, we compared both results to identify common regulatory patterns of Cesarean section and islet autoimmunity at the gene expression level.ResultsWe identified two differentially expressed pathways in children born by Cesarean section: the pentose phosphate pathway and pyrimidine metabolism, both involved in nucleotide synthesis and cell proliferation. Islet autoantibody analysis revealed multiple differentially expressed pathways generally involved in immune processes, including both of the above-mentioned nucleotide synthesis pathways. Comparison of global gene expression signatures showed that transcriptomic changes were systematically and significantly correlated between Cesarean section and islet autoimmunity. In addition, signatures of both Cesarean section and islet autoimmunity correlated with transcriptional changes observed during activation of isolated CD4+ T lymphocytes.ConclusionsWe identified coherent gene expression signatures for Cesarean section, an early risk factor for type 1 diabetes, and islet autoantibodies positivity, an obligatory stage of autoimmune response prior to the development of type 1 diabetes. Both transcriptional signatures were correlated with changes in gene expression during the activation of CD4+ T lymphocytes, reflecting common molecular changes in immune cell activation.

291-OR: Deletion within the Helicase 1 Domain of MDA5 Dampens Immune Cell Activation and Delays Type 1 Diabetes

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 291-OR
Author(s):  
SAMUEL I. BLUM ◽  
YI-GUANG CHEN ◽  
HUBERT M. TSE
Keyword(s):  
Type 1 Diabetes ◽  
Cell Activation ◽  
Immune Cell ◽  
Immune Cell Activation

scholarly journals PD-L1 and tumor-associated macrophages in de novo DLBCL

2019 ◽  
Vol 3 (4) ◽  
pp. 531-540 ◽  
Author(s):  
Ronald McCord ◽  
Christopher R. Bolen ◽  
Hartmut Koeppen ◽  
Edward E. Kadel ◽  
Mikkel Z. Oestergaard ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Activation ◽  
Immune Cell ◽  
De Novo ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Staining Procedure ◽  
Immune Cell Activation ◽  
Improved Outcomes ◽  
Risk Patients

Abstract Programmed death-ligand 1 (PD-L1) and its receptor, programmed cell death-1 (PD-1), are important negative regulators of immune cell activation. Therapeutically targeting PD-1/PD-L1 in diffuse large B-cell lymphoma (DLBCL) patients with a single agent has limited activity, meriting a deeper understanding of this complex biology and of available PD-L1 clinical assays. In this study, we leveraged 2 large de novo DLBCL phase 3 trials (GOYA and MAIN) to better understand the biologic and clinical relevance of PD-L1 in de novo DLBCL. PD-L1 was expressed on myeloid cells in 85% to 95% of DLBCL patients (depending on staining procedure), compared with 10% on tumor cells, and correlated with macrophage gene expression. PD-L1 did not identify high-risk patients in de novo DLBCL; it correlated with STAT3, macrophage gene expression, and improved outcomes among a subset of patients. These results may help identify immunologically distinct DLBCL subsets relevant for checkpoint blockade. GOYA and MAIN trials were registered at www.clinicaltrials.gov as #NCT01287741 and #NCT00486759, respectively.

scholarly journals miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Martin G. Scherm ◽  
Isabelle Serr ◽  
Adam M. Zahm ◽  
Jonathan Schug ◽  
Saverio Bellusci ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
T Cell Activation ◽  
Pancreatic Beta Cells ◽  
Cell Activation ◽  
Clinical Symptoms ◽  
Mechanistic Model ◽  
Treg Cells ◽  
Islet Autoimmunity ◽  
Molecular Approaches

AbstractIn type 1 diabetes, the appearance of islet autoantibodies indicates the onset of islet autoimmunity, often many years before clinical symptoms arise. While T cells play a major role in the destruction of pancreatic beta cells, molecular underpinnings promoting aberrant T cell activation remain poorly understood. Here, we show that during islet autoimmunity an miR142-3p/Tet2/Foxp3 axis interferes with the efficient induction of regulatory T (Treg) cells, resulting in impaired Treg stability in mouse and human. Specifically, we demonstrate that miR142-3p is induced in islet autoimmunity and that its inhibition enhances Treg induction and stability, leading to reduced islet autoimmunity in non-obese diabetic mice. Using various cellular and molecular approaches we identify Tet2 as a direct target of miR142-3p, thereby linking high miR142-3p levels to epigenetic remodeling in Tregs. These findings offer a mechanistic model where during islet autoimmunity miR142-3p/Tet2-mediated Treg instability contributes to autoimmune activation and progression.

Antibody Inhibition of HIV-1 Transmission from Antigen-presenting Cells to CD4 T Lymphocytes Involves Immune Cell Activation

2014 ◽  
Vol 30 (S1) ◽  
pp. A154-A154
Author(s):  
Bin Su ◽  
Alexandre Lederle ◽  
Géraldine Laumond ◽  
Sylvie Schmidt ◽  
Thomas Decoville ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cell Activation ◽  
Immune Cell ◽  
Antigen Presenting Cells ◽  
Immune Cell Activation ◽  
Antigen Presenting ◽  
Antibody Inhibition ◽  
Hiv 1

scholarly journals An HLA-Transgenic Mouse Model of Type 1 Diabetes That Incorporates the Reduced but Not Abolished Thymic Insulin Expression Seen in Patients

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Jeffrey Babad ◽  
Riyasat Ali ◽  
Jennifer Schloss ◽  
Teresa P. DiLorenzo
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Beta Cells ◽  
Immune Cell ◽  
Regulatory Region ◽  
Islet Autoimmunity ◽  
Positive Type ◽  
Insulin Expression ◽  
Pancreatic Islet Beta Cells

Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of the pancreatic islet beta cells. Multiple genetic loci contribute to disease susceptibility in humans, with the most responsible locus being the major histocompatibility complex (MHC). Certain MHC alleles are predisposing, including the common HLA-A∗02:01. After the MHC, the locus conferring the strongest susceptibility to T1D is the regulatory region of the insulin gene, and alleles associated with reduced thymic insulin expression are predisposing. Mice express two insulin genes,Ins1andIns2. While both are expressed in beta cells, onlyIns2is expressed in the thymus. We have developed an HLA-A∗02:01-transgenic NOD-based T1D model that is heterozygous for a functionalIns2gene. These mice exhibit reduced thymic insulin expression and accelerated disease in both genders. Immune cell populations are not grossly altered, and the mice exhibit typical signs of islet autoimmunity, including CD8 T cell responses to beta cell peptides also targeted in HLA-A∗02:01-positive type 1 diabetes patients. This model should find utility as a tool to uncover the mechanisms underlying the association between reduced thymic insulin expression and T1D in humans and aid in preclinical studies to evaluate insulin-targeted immunotherapies for the disease.

Cytotoxicity-related gene expression and chromatin accessibility define a subset of CD4+ T cells that mark progression to type 1 diabetes

Diabetes ◽  
2022 ◽  
Author(s):  
Naiara G. Bediaga ◽  
Alexandra L. Garnham ◽  
Gaetano Naselli ◽  
Esther Bandala-Sanchez ◽  
Natalie L. Stone ◽  
...  
Keyword(s):  
Gene Expression ◽  
At Risk ◽  
T Cells ◽  
Type 1 Diabetes ◽  
Cd4 T Cells ◽  
Chromatin Accessibility ◽  
Differentially Expressed ◽  
Islet Autoimmunity ◽  
At Risk Children

Type 1 diabetes in children is heralded by a preclinical phase defined by circulating autoantibodies to pancreatic islet antigens. How islet autoimmunity is initiated and then progresses to clinical diabetes remains poorly understood. Only one study has reported gene expression in specific immune cells of at-risk children, associated with progression to islet autoimmunity. We analysed gene expression by RNAseq in CD4+ and CD8+ T cells, NK cells and B cells, and chromatin accessibility by ATACseq in CD4+ T cells, in five genetically at-risk children with islet autoantibodies who progressed to diabetes over a median of 3 years (‘Progressors’) compared to five children matched for sex, age and HLA-DR who had not progressed (‘Non-progressors). In Progressors, differentially expressed genes (DEGs) were largely confined to CD4+ T cells and enriched for cytotoxicity-related genes/pathways. Several top-ranked DEGs were validated in a semi-independent cohort of 13 Progressors and 11 Non-progressors. Flow cytometry confirmed progression was associated with expansion of CD4+ cells with a cytotoxic phenotype. By ATAC-seq, progression was associated with reconfiguration of regulatory chromatin regions in CD4+ T cells, some linked to differentially expressed cytotoxicity-related genes. Our findings suggest that cytotoxic CD4+ T cells play a role in promoting progression to type 1 diabetes.

Cytotoxicity-related Gene Expression and Chromatin Accessibility Define a Subset of CD4+ T Cells that Mark Progression to Type 1 Diabetes

2022 ◽  
Author(s):  
Naiara G. Bediaga ◽  
Alexandra L. Garnham ◽  
Gaetano Naselli ◽  
Esther Bandala-Sanchez ◽  
Natalie L. Stone ◽  
...  
Keyword(s):  
Gene Expression ◽  
At Risk ◽  
T Cells ◽  
Type 1 Diabetes ◽  
Chromatin Accessibility ◽  
Differentially Expressed ◽  
Islet Autoimmunity ◽  
Preclinical Phase ◽  
At Risk Children

Type 1 diabetes in children is heralded by a preclinical phase defined by circulating autoantibodies to pancreatic islet antigens. How islet autoimmunity is initiated and then progresses to clinical diabetes remains poorly understood. Only one study has reported gene expression in specific immune cells of at-risk children, associated with progression to islet autoimmunity. We analysed gene expression by RNAseq in CD4<sup>+</sup> and CD8<sup>+</sup> T cells, NK cells and B cells, and chromatin accessibility by ATACseq in CD4<sup>+</sup> T cells, in five genetically at-risk children with islet autoantibodies who progressed to diabetes over a median of 3 years (‘Progressors’) compared to five children matched for sex, age and HLA-DR who had not progressed (‘Non-progressors). In Progressors, differentially expressed genes (DEGs) were largely confined to CD4<sup>+</sup> T cells and enriched for cytotoxicity-related genes/pathways. Several top-ranked DEGs were validated in a semi-independent cohort of 13 Progressors and 11 Non-progressors. Flow cytometry confirmed progression was associated with expansion of CD4<sup>+ </sup>cells with a cytotoxic phenotype. By ATAC-seq, progression was associated with reconfiguration of regulatory chromatin regions in CD4<sup>+ </sup>cells, some linked to differentially expressed cytotoxicity-related genes. Our findings suggest that cytotoxic CD4<sup>+ </sup>T cells play a role in promoting progression to type 1 diabetes.

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