A variant of the PTPN22 gene, 1858C/T, is associated with an increased risk for the development of a wide array of autoimmune disorders. It is known that the protein tyrosine phosphatase Lyp encoded by this gene has an inhibitory effect on the proximal TCR signaling pathways. However, the consequences of carrying this variant and the mechanism by which it contributes to the development of autoimmunity are poorly understood. In this study, we demonstrate that homozygosity for this variant results in a profound deficit in T cell responsiveness to Ag stimulation. Heterozygosity for the variant allele is associated with reduced responsiveness of CD4+ memory T cells, characterized by diminished calcium mobilization, expression of CD25, and IL-10 production upon TCR stimulation. Additionally, the presence of the variant allele is associated with an increase in circulating memory T cells. We further demonstrate that these effects are not limited to the T cell compartment. Individuals with the variant allele have fewer memory B cells and these cells display a reduced response to stimulation via the BCR indicative of a B cell intrinsic defect. By identifying an immunologic phenotype in healthy subjects which correlates with the PTPN22 1858C/T genotype, we can now explore specific hypotheses regarding pathogenesis of diseases associated with the PTPN22 1858T variant.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.4049/jimmunol.179.7.4704 | DOI Listing |
Hum Genomics
January 2025
Department of Biology, Tor Vergata University of Rome, Via della Ricerca Scientifica 1, 00133, Rome, Italy.
Background: The Immunoglobulin Heavy Chain (IGH) genomic region is responsible for the production of circulating antibodies and warrants careful investigation for its association with COVID-19 characteristics. Multiple allelic variants within and across different IGH gene segments form a limited set of haplotypes. Previous studies have shown associations between some of these haplotypes and clinical outcomes of COVID-19.
View Article and Find Full Text PDFBMC Genomics
January 2025
Department of Population Health and Reproduction, Davis School of Veterinary Medicine, University of California, Room 4206 Vet Med3A One Shields Ave, Davis, CA, 95616, USA.
Background: Allele-specific expression (ASE) analysis provides a nuanced view of cis-regulatory mechanisms affecting gene expression.
Results: An equine ASE analysis was performed, using integrated Iso-seq and short-read RNA sequencing data from four healthy Thoroughbreds (2 mares and 2 stallions) across 9 tissues from the Functional Annotation of Animal Genomes (FAANG) project. Allele expression was quantified by haplotypes from long-read data, with 42,900 allele expression events compared.
Patients with end-stage renal disease (ESRD) are at a higher risk of cardiovascular (CV) complications and mortality compared to the general population. This study aimed to investigate the genetic polymorphisms of KCNN2, a key gene encoding a subtype of small-conductance calcium-activated potassium (SK) channels, which regulate an important SK current pathway potentially involved in the development of CV complications, particularly arrhythmias, in ESRD patients. A total of 169 ESRD patients were enrolled in this study.
View Article and Find Full Text PDFInvest Ophthalmol Vis Sci
January 2025
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China.
Purpose: The purpose of this study was to investigate the contribution and natural progression of ABCA4 deep intronic variants (DIVs) among a Chinese Stargardt disease (STGD) cohort.
Methods: For unsolved STGD probands, DIVs in ABCA4 were detected by next-generation sequencing, and splicing effects were evaluated by in silico tools and validated through minigene experiments. Comprehensive ocular examinations, especially fundus changes, were carried out and analyzed.
Dis Model Mech
January 2025
Divisions of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Gsx2 is a homeodomain transcription factor critical for development of the ventral telencephalon and hindbrain of the mouse. Loss of Gsx2 function results in severe basal ganglia dysgenesis as well as defects in the nucleus tractus solitarius (nTS) of the hindbrain together with respiratory failure at birth. De Mori et al.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!