Editorial: Genetic basis of tolerance induction defects underlying the development of autoimmune pathologies.
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ABSTRACT:
SUBMITTER: Racine JJ
PROVIDER: S-EPMC9644883 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
Editorial: Genetic basis of tolerance induction defects underlying the development of autoimmune pathologies.
Racine Jeremy J JJ Morel Laurence L Chen Yi-Guang YG Serreze David V DV
Frontiers in immunology 20221026
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Project description:Genetic variants associated with susceptibility to autoimmune disease have provided important insight into the mechanisms responsible for the loss of immune tolerance and the subsequent development of autoantibodies, tissue damage, and onset of clinical disease. Here, we review how genetic variants shared across multiple autoimmune diseases have contributed to our understanding of global tolerance failure, focusing on variants in the human leukocyte antigen region, PTPN2 and PTPN22, and their role in antigen presentation and T and B cell homeostasis. Variants unique to a specific autoimmune disease such as those in PADI2 and PADI4 that are associated with rheumatoid arthritis are also discussed, addressing their role in disease-specific immunopathology. Current research continues to focus on determining the functional consequences of autoimmune disease-associated variants but has recently expanded to variants in the non-coding regions of the genome using novel approaches to investigate the impact of these variants on mechanisms regulating gene expression. Lastly, studying genetic risk variants in the setting of autoimmunity has clinical implications, helping predict who will develop autoimmune disease and also identifying potential therapeutic targets.
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Project description:PurposePrimary B cell defects manifesting as predominantly antibody deficiencies result from variable inborn errors of the B cell lineage and their development, including impairments in early bone marrow development, class switch recombination (CSR), or terminal B cell differentiation. In this study, we aimed to investigate autoimmunity in monogenic patients with B cell development and differentiation defects.MethodsPatients with known genetic defects in the B cell development and differentiation were recruited from the Iranian inborn errors of immunity registry.ResultsA total of 393 patients with a known genetic defect in the B cell development and differentiation (257 males; 65.4%) with a median age of 12 (6-20) years were enrolled in this study. After categorizing patients, 109 patients had intrinsic B cell defects. More than half of the patients had defects in one of the ATM (85 patients), BTK (76 patients), LRBA (34 patients), and DOCK8 (33 patients) genes. Fifteen patients (3.8%) showed autoimmune complications as their first manifestation. During the course of the disease, autoimmunity was reported in 81 (20.6%) patients at a median age of 4 (2-7) years, among which 65 patients had mixed intrinsic and extrinsic and 16 had intrinsic B cell defects. The comparison between patients with the mentioned four main gene defects showed that the patient group with LRBA defect had a significantly higher frequency of autoimmunity compared to those with other gene defects. Based on the B cell defect stage, 13% of patients with early B cell defect, 17% of patients with CSR defect, and 40% of patients who had terminal B cell defect presented at least one type of autoimmunity.ConclusionOur results demonstrated that gene mutations involved in human B cell terminal stage development mainly LRBA gene defect have the highest association with autoimmunity.
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Project description:The proteomic profiling of apple spur buds aimed to reveal the proteomic differences between the trees with (ON) and without (OFF) crop load.
2021-03-25 | PXD021716 | Pride
Project description:BackgroundCyanobacteria constitute a serious threat to freshwater ecosystems by producing toxic secondary metabolites, e.g. microcystins. These microcystins have been shown to harm livestock, pets and humans and to affect ecosystem service and functioning. Cyanobacterial blooms are increasing worldwide in intensity and frequency due to eutrophication and global warming. However, Daphnia, the main grazer of planktonic algae and cyanobacteria, has been shown to be able to suppress bloom-forming cyanobacteria and to adapt to cyanobacteria that produce microcystins. Since Daphnia's genome was published only recently, it is now possible to elucidate the underlying molecular mechanisms of microcystin tolerance of Daphnia.ResultsDaphnia magna was fed with either a cyanobacterial strain that produces microcystins or its genetically engineered microcystin knock-out mutant. Thus, it was possible to distinguish between effects due to the ingestion of cyanobacteria and effects caused specifically by microcystins. By using RNAseq the differentially expressed genes between the different treatments were analyzed and affected KOG-categories were calculated. Here we show that the expression of transporter genes in Daphnia was regulated as a specific response to microcystins. Subsequent qPCR and dietary supplementation with pure microcystin confirmed that the regulation of transporter gene expression was correlated with the tolerance of several Daphnia clones.ConclusionsHere, we were able to identify new candidate genes that specifically respond to microcystins by separating cyanobacterial effects from microcystin effects. The involvement of these candidate genes in tolerance to microcystins was validated by correlating the difference in transporter gene expression with clonal tolerance. Thus, the prevention of microcystin uptake most probably constitutes a key mechanism in the development of tolerance and adaptation of Daphnia. With the availability of clear candidate genes, future investigations examining the process of local adaptation of Daphnia populations to microcystins are now possible.
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Project description:Children with newly diagnosed ITP that after 12 month enter remission, shows molecular separate entities. The molecular basis for remission and tolerance induction is characterized by gene transcriptional profiling Global gene expression profile in isolated T-cells from 6 children with newly diagnosed ITP and after 12 month when they enter remission
2016-02-06 | E-GEOD-56232 | biostudies-arrayexpress
Project description:Aneuploidy, in which cells carry an abnormal chromosome count, is detrimental during development yet common in human cancers; why cells differ in tolerance remains unclear. We mapped the genetic basis of aneuploidy tolerance in wild Saccharomyces cerevisiae versus the sensitive lab strain to Ssd1, an RNA-binding protein involved in translation whose loss recapitulates aneuploidy signatures in laboratory yeast. We find Ssd1 localizes to mitochondria, influences localization of nuclear-encoded mitochondrial mRNAs and/or abundance of the encoded proteins, influences mitochondrial function, and minimizes protein aggregates upon chromosome amplification. Recapitulating ssd1D defects with combinatorial drug treatment selectively targets wild-type aneuploids in multiple strains, suggesting therapeutic approaches. Our work adds to elegant studies done in the sensitized laboratory strain to present a mechanistic understanding of aneuploidy tolerance in eukaryotes.
2020-01-08 | GSE132425 | GEO