scholarly journals Method for identification of condition-associated public antigen receptor sequences

2017 ◽  
Author(s):  
M.V. Pogorelyy ◽  
A.A. Minervina ◽  
D.M. Chudakov ◽  
I.Z. Mamedov ◽  
Y.B. Lebedev ◽  
...  
Keyword(s):  
Association Studies ◽  
Antigen Receptor ◽  
Adaptive Immune System ◽  
Immunoglobulin Receptor ◽  
Receptor Repertoire ◽  
Statistical Framework ◽  
Repertoire Sequencing ◽  
Small Cohort ◽  
Immunoglobulin Receptors

Diverse repertoires of hypervariable immunoglobulin receptors (TCR and BCR) recognize antigens in the adaptive immune system. The development of immunoglobulin receptor repertoire sequencing methods makes it possible to perform repertoire-wide disease association studies of antigen receptor sequences. We developed a statistical framework for associating receptors to disease from only a small cohort of patients, with no need for a control cohort. Our method successfully identifies previously validated Cytomegalovirus and type 1 diabetes responsive receptors.

scholarly journals Method for identification of condition-associated public antigen receptor sequences

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Mikhail V Pogorelyy ◽  
Anastasia A Minervina ◽  
Dmitriy M Chudakov ◽  
Ilgar Z Mamedov ◽  
Yuri B Lebedev ◽  
...  
Keyword(s):  
Association Studies ◽  
Antigen Receptor ◽  
Adaptive Immune System ◽  
Immunoglobulin Receptor ◽  
Receptor Repertoire ◽  
Statistical Framework ◽  
Type One Diabetes ◽  
Repertoire Sequencing ◽  
Small Cohort ◽  
Immunoglobulin Receptors

Diverse repertoires of hypervariable immunoglobulin receptors (TCR and BCR) recognize antigens in the adaptive immune system. The development of immunoglobulin receptor repertoire sequencing methods makes it possible to perform repertoire-wide disease association studies of antigen receptor sequences. We developed a statistical framework for associating receptors to disease from only a small cohort of patients, with no need for a control cohort. Our method successfully identifies previously validated Cytomegalovirus and type one diabetes responsive TCRβ sequences .

scholarly journals Corrigendum: FB5P-seq: FACS-Based 5-Prime End Single-Cell RNA-seq for Integrative Analysis of Transcriptome and Antigen Receptor Repertoire in B and T Cells

2020 ◽  
Vol 11 ◽  
Author(s):  
Noudjoud Attaf ◽  
Iñaki Cervera-Marzal ◽  
Chuang Dong ◽  
Laurine Gil ◽  
Amédée Renand ◽  
...  
Keyword(s):  
T Cells ◽  
Single Cell ◽  
Antigen Receptor ◽  
Integrative Analysis ◽  
Rna Seq ◽  
Receptor Repertoire ◽  
Prime End

scholarly journals A comprehensive integrated post-GWAS analysis of Type 1 diabetes reveals enhancer-based immune dysregulation

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257265
Author(s):  
Seung-Soo Kim ◽  
Adam D. Hudgins ◽  
Jiping Yang ◽  
Yizhou Zhu ◽  
Zhidong Tu ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Target Genes ◽  
Association Studies ◽  
Regulatory Elements ◽  
Immune Dysregulation ◽  
Specific Gene ◽  
Genome Wide Association Studies ◽  
Gwas Analysis ◽  
Regulatory Variants

Type 1 diabetes (T1D) is an organ-specific autoimmune disease, whereby immune cell-mediated killing leads to loss of the insulin-producing β cells in the pancreas. Genome-wide association studies (GWAS) have identified over 200 genetic variants associated with risk for T1D. The majority of the GWAS risk variants reside in the non-coding regions of the genome, suggesting that gene regulatory changes substantially contribute to T1D. However, identification of causal regulatory variants associated with T1D risk and their affected genes is challenging due to incomplete knowledge of non-coding regulatory elements and the cellular states and processes in which they function. Here, we performed a comprehensive integrated post-GWAS analysis of T1D to identify functional regulatory variants in enhancers and their cognate target genes. Starting with 1,817 candidate T1D SNPs defined from the GWAS catalog and LDlink databases, we conducted functional annotation analysis using genomic data from various public databases. These include 1) Roadmap Epigenomics, ENCODE, and RegulomeDB for epigenome data; 2) GTEx for tissue-specific gene expression and expression quantitative trait loci data; and 3) lncRNASNP2 for long non-coding RNA data. Our results indicated a prevalent enhancer-based immune dysregulation in T1D pathogenesis. We identified 26 high-probability causal enhancer SNPs associated with T1D, and 64 predicted target genes. The majority of the target genes play major roles in antigen presentation and immune response and are regulated through complex transcriptional regulatory circuits, including those in HLA (6p21) and non-HLA (16p11.2) loci. These candidate causal enhancer SNPs are supported by strong evidence and warrant functional follow-up studies.

scholarly journals High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy

2016 ◽  
Vol 113 (8) ◽  
pp. 2218-2222 ◽  
Author(s):  
Catherine K. Hathaway ◽  
Albert S. Chang ◽  
Ruriko Grant ◽  
Hyung-Suk Kim ◽  
Victoria J. Madden ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Transforming Growth Factor ◽  
Association Studies ◽  
Lipid Peroxides ◽  
Transforming Growth Factor Β1 ◽  
Genome Wide Association Studies ◽  
Diabetic Mice ◽  
Stage Renal Disease ◽  
End Stage

Human genome-wide association studies have demonstrated that polymorphisms in the engulfment and cell motility protein 1 gene (ELMO1) are strongly associated with susceptibility to diabetic nephropathy. However, proof of causation is lacking. To test whether modest changes in its expression alter the severity of the renal phenotype in diabetic mice, we have generated mice that are type 1 diabetic because they have the Ins2Akita gene, and also have genetically graded expression of Elmo1 in all tissues ranging in five steps from ∼30% to ∼200% normal. We here show that the Elmo1 hypermorphs have albuminuria, glomerulosclerosis, and changes in the ultrastructure of the glomerular basement membrane that increase in severity in parallel with the expression of Elmo 1. Progressive changes in renal mRNA expression of transforming growth factor β1 (TGFβ1), endothelin-1, and NAD(P)H oxidase 4 also occur in parallel with Elmo1, as do the plasma levels of cystatin C, lipid peroxides, and TGFβ1, and erythrocyte levels of reduced glutathione. In contrast, Akita type 1 diabetic mice with below-normal Elmo1 expression have reduced expression of these various factors and less severe diabetic complications. Remarkably, the reduced Elmo1 expression in the 30% hypomorphs almost abolishes the pathological features of diabetic nephropathy, although it does not affect the hyperglycemia caused by the Akita mutation. Thus, ELMO1 plays an important role in the development of type 1 diabetic nephropathy, and its inhibition could be a promising option for slowing or preventing progression of the condition to end-stage renal disease.

Attenuated Asthma Phenotype in Mice With a Fetal-Like Antigen Receptor Repertoires

2021 ◽  
Author(s):  
Regine Stutz ◽  
Christopher Meyer ◽  
Elisabeth Kaiser ◽  
Sybelle Goedicke-Fritz ◽  
Harry Schroeder ◽  
...  
Keyword(s):  
Antigen Receptor ◽  
Allergic Airway Inflammation ◽  
Cell Receptor ◽  
Lung Function Test ◽  
Antigen Receptors ◽  
Asthma Phenotype ◽  
Receptor Repertoire ◽  
Repertoire Diversity ◽  
Cytokine Milieu ◽  
Respiratory Inflammation

Abstract We hypothesized that the scarcity of N-nucleotides might contribute to the inability of the neonate to mount a robust allergic immune response. To test this, we used terminal deoxyribunucleotidyl Transferase deficient (TdT-/-) mice, which express “fetal like” T cell receptor and immunoglobulin repertoires with largely germline-encoded CDR3 regions.Intraperitoneal sensitization was followed by aerosol provocation with either PBS or the allergen OVA in both Tdt-/- mice and wild-type mice to develop allergic respiratory inflammation. The effects of this procedure were investigated by lung function test, immunological analysis of serum and brochoalveolar lavage. The local TH2 cytokine milieu was significantly attenuated in Tdt-/- mice. Within this group, the induction of total IgE levels was also significantly reduced after sensitization. Tdt-/- mice showed a reduced eosinophilic inflow into the bronchial tubes, which was associated with the elimination of respiratory hyperreactivity. In conclusion, in a murine model of allergic airway inflammation, the expression of fetal-like antigen receptors was associated with a reduced ability to mount an asthma phenotype. This underlines the importance of somatically-generated antigen-receptor repertoire diversity in type one allergic immune responses and suggests that the fetus may be protected from allergic responses, at least in part, by controlling N addition.

Association of HLA Class II Alleles and Haplotypes with Type 1 Diabetes in Tunisian Arabs

2018 ◽  
Vol 127 (10) ◽  
pp. 653-662
Author(s):  
Abdelhafidh Hajjej ◽  
Wassim Y. Almawi ◽  
Mouna Stayoussef ◽  
Lasmar Hattab ◽  
Slama Hmida
Keyword(s):  
Type 1 Diabetes ◽  
Association Studies ◽  
Class Ii ◽  
Correlation Study ◽  
Case Control ◽  
Linkage Study ◽  
Hla Class Ii ◽  
Racial Background ◽  
Family Based

AbstractThe molecular association of HLA class II with type 1 diabetes (T1DM) was investigated in Tunisian Arabs using 3 kinds of analyses. The first was a case-control association study, using Relative Predispositional Effects method, involved 137 T1DM cases and 258 control subjects. The second was family-based association-linkage study, using Transmission Disequilibrium Test, and covering 50 Tunisian families comprising 73 T1DM patients and 100 parents. The third was a wide correlation study between 4 DRB1 alleles (DRB1*03, *04, *11, *15) and T1DM in 52 countries, using Spearman’s Rho. Results from Case-control and family-based association studies showed that DRB1*03 and DRB1*04 alleles predispose to T1DM in Tunisian Arabs. Conversely, only DRB1*11 was protective for T1DM. DRB1*04-DQB1*03 haplotype was consistently associated positively with T1DM; DRB1*03/DRB1*04 genotype had the highest risk of T1DM development. Compared to DRB1*03, HLA-DRB1*04 was associated with higher T1DM incidence. Thus, the contribution of HLA class II to T1DM genetic susceptibility must be evaluated with regards to specific HLA alleles, genotypes, and haplotypes, and also ethnic and racial background.

scholarly journals Regulatory T cells engineered with a novel insulin-specific chimeric antigen receptor as a candidate immunotherapy for type 1 diabetes

2019 ◽  
Vol 103 ◽  
pp. 102289 ◽  
Author(s):  
Michel Tenspolde ◽  
Katharina Zimmermann ◽  
Leonie C. Weber ◽  
Martin Hapke ◽  
Maren Lieber ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Regulatory T Cells ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor

NKX2.5/NKX2.6 Mutations Are Not a Common Cause of Isolated Type 1 Truncus Arteriosus in a Small Cohort of Multiethnic Cases

2008 ◽  
Vol 12 (4) ◽  
pp. 467-469 ◽  
Author(s):  
Maher Khetyar ◽  
Lorna Tinworth ◽  
Petros Syrris ◽  
Lulu Abushaban ◽  
Yousef Abdulazzaq ◽  
...  
Keyword(s):  
Truncus Arteriosus ◽  
Common Cause ◽  
Small Cohort
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