Single-cell RNA sequencing of IkbkbV203I Tregs from spleen and bone marrow
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE228385 | GEO | 2024/01/09
REPOSITORIES: GEO
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Project description:Loss-of-function mutations have provided crucial insights into the immunoregulatory actions of Foxp3+ regulatory T cells (Tregs). By contrast, we know very little about the consequences of defects that amplify aspects of Treg function or differentiation. We report that mice heterozygous for an Ikbkb gain-of-function (GoF) mutation develop psoriasis. Doubling the gene dose (IkbkbGoF/GoF) results in dactylitis, spondylitis, and characteristic nail changes, which are features of psoriatic arthritis. IkbkbGoF mice exhibit a selective expansion of Foxp3+ CD25+ Tregs of which a subset express IL-17. These modified Tregs were enriched at the inflamed tissues and spleen, and their transfer was sufficient to induce disease without conventional T cells. Single-cell transcriptional and phenotyping analyses of isolated Tregs revealed expansion of non-lymphoid tissue (tissue-resident) Tregs expressing Th17-related genes, Helios, tissue-resident markers including CD103 and CD69, and a prominent NF-kB transcriptome. Thus, IKK2 regulates tissue-resident Treg differentiation, and overactivity drives dose-dependent skin and systemic inflammation.
2024-01-09 | GSE248917 | GEO
Project description:Psoriasis is a common, immune-mediated, genetic disorder of the skin associated with arthritis in approximately 30% of cases. Previously, we localized PSORS2 (psoriasis susceptibility locus 2) to chromosome 17q25.3-qter following a genome-wide linkage scan in a family of European origin with multiple cases of psoriasis and psoriatic arthritis. Linkage to PSORS2 was also observed in a multiply affected psoriasis family from Taiwan. With genomic capture and DNA sequencing, we identified unique gain-of-function mutations in caspase recruitment domain family, member 14 (CARD14) that segregated with psoriasis. The mutations, c.349G>A (p.Gly117Ser) and c.349+5G>A respectively, altered splicing between exons 3 and 4 of CARD14. A de novo mutation in CARD14, c.413A>C [p.Glu138Ala], was detected in a child with sporadic, early-onset, generalized pustular psoriasis. CARD14 activates nuclear factor kappa B (NF-kB), and the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes compared to wildtype CARD14. These included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, while in lesional psoriatic skin it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the lesional epidermis. We propose that, following a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration that is the hallmark of psoriasis. No replicates are included. Three sample sets. [1] Skin biopsies had RNA extracted for expression within target tissue. [2] HEK cells were transfected with different constructs (including wildtype) of CARD14 to determine the mutational effect in keratinocytes. [3] Keratinocytes derived from psoriasis patients with CARD14 mutations were cultured and compared with and without stimulation with TNFalpha.
2012-05-08 | E-GEOD-36387 | biostudies-arrayexpress
Project description:Psoriasis is a common, immune-mediated, genetic disorder of the skin associated with arthritis in approximately 30% of cases. Previously, we localized PSORS2 (psoriasis susceptibility locus 2) to chromosome 17q25.3-qter following a genome-wide linkage scan in a family of European origin with multiple cases of psoriasis and psoriatic arthritis. Linkage to PSORS2 was also observed in a multiply affected psoriasis family from Taiwan. With genomic capture and DNA sequencing, we identified unique gain-of-function mutations in caspase recruitment domain family, member 14 (CARD14) that segregated with psoriasis. The mutations, c.349G>A (p.Gly117Ser) and c.349+5G>A respectively, altered splicing between exons 3 and 4 of CARD14. A de novo mutation in CARD14, c.413A>C [p.Glu138Ala], was detected in a child with sporadic, early-onset, generalized pustular psoriasis. CARD14 activates nuclear factor kappa B (NF-kB), and the p.Gly117Ser and p.Glu138Ala substitutions were shown to lead to enhanced NF-kB activation and upregulation of a subset of psoriasis-associated genes in keratinocytes compared to wildtype CARD14. These included chemokine (C-C motif) ligand 20 (CCL20) and interleukin 8 (IL8). CARD14 is localized mainly in the basal and suprabasal layers of healthy skin epidermis, while in lesional psoriatic skin it is reduced in the basal layer and more diffusely upregulated in the suprabasal layers of the lesional epidermis. We propose that, following a triggering event that can include epidermal injury, rare gain-of-function mutations in CARD14 initiate a process that includes inflammatory cell recruitment by keratinocytes. This perpetuates a vicious cycle of epidermal inflammation and regeneration that is the hallmark of psoriasis.
2012-05-09 | GSE36387 | GEO
Project description:In order to analyze and find differentially expressed circRNAs in Treg from psoriatic and healthy controls, we aimed to explore whether differentially expressed circRNAs in psoriatic patients could account for the dysfunctional Tregs in psoriasis patients could account for dysfunctional Tregs in psoriatic patients
2020-07-22 | GSE154818 | GEO
Project description:Psoriasis is a chronic inflammatory disease of the skin for which current treatments are only partially effective. There is therefore an urgent need to develop novel therapies with higher efficacy through a better understanding of disease aetiology. Recently, it has been demonstrated that individuals with specific mutations in the gene encoding the adapter protein CARD14 have a high risk of developing psoriasis. Psoriasis associated CARD14 mutations result in enhanced activation of NF-kB transcription factors in keratinocytes. The CARD14/NF-kB axis may therefore be central in driving the pathogenesis of psoriasis. The aim of this project is to investigate the molecular mechanisms by which CARD14 activates the NF-kB pathway. Specifically, within this project, we aim to detail the interaction partners of both WT and a gain-of-function mutant CARD14 (E138A) via SILAC and mass spectrometry.
2024-08-27 | PXD033039 | Pride
Project description:Psoriasis is a chronic inflammatory disease of the skin for which current treatments are only partially effective. There is therefore an urgent need to develop novel therapies with higher efficacy through a better understanding of disease aetiology. Recently, it has been demonstrated that individuals with specific mutations in the gene encoding the adapter protein CARD14 have a high risk of developing psoriasis. Psoriasis associated CARD14 mutations result in enhanced activation of NF-kB transcription factors in keratinocytes. The CARD14/NF-kB axis may therefore be central in driving the pathogenesis of psoriasis. The aim of this project is to investigate the molecular mechanisms by which CARD14 activates the NF-kB pathway. Specifically, within this project, we aim to detail the downstream signalling pathways of a gain-of-function mutant CARD14 (E138A) via SILAC and mass spectrometry.
2024-08-27 | PXD033009 | Pride
Project description:We report changes in gene expression in human peripheral blood neutrophils from patients with psoriatic arthritis (PsA) before and 12-weeks after treatment with Secukinumab (SKB, 150mg). All patients achieved a good PSARC (Psoriatic Arthritis Response Criteria) and PASI 90 (Psoriasis Area and Severity Index) response to treatment. We also report gene expression in healthy control neutrophils compared to patients wth psoriatic arthritis.
2023-01-06 | GSE179800 | GEO
Project description:<p>The GEI Studies Project was started as an NIH consortium involving 5 disease groups with funding provided through the Genes, Environment, and Health Initiative (GEI). The objective of the project was to optimize strategies for identifying rare variants as a follow up to genome-wide association studies (GWAS) using next-generation sequencing technology. One of the five targeted diseases, Psoriasis, is a multifactorial skin disease characterized by epidermal hyperproliferation and chronic inflammation that affects approximately 2% of Americans. Because only about one-third of all patients with psoriasis have a relative who is also affected with the disorder, psoriasis is not widely recognized as a genetic disease. However, previous research on families and identical twins has shown psoriasis has a strong genetic component, although environmental factors (such as infections, stress, and injuries) are also important. Although no definite psoriasis gene has yet been identified, research during the last ten years has revealed over forty potential gene locations that may contribute to the disease. Large amounts of data generated using next-generation sequencing technology would provide a more detailed characterization of sequence variation which would in turn increase the likelihood of detecting causative loci. With the presumption that rare variants are frequently the cause of a large portion of phenotypic variation, it was necessary to use large sample sets. In the main body of this study, we sequenced 4,966 samples (812 dermatologist-diagnosed cases of purely cutaneous psoriasis (PsC), 1,497 cases of rheumatologist-diagnosed psoriatic arthritis, 665 cases of cutaneous psoriasis with uncertain psoriatic arthritis status (PsV) and 1,992 controls) across 5.7 Mb of sequence containing 100 psoriasis candidate loci and 769 genes. For each candidate locus, we considered sequences within 250 kb of the strongest association signal. Within this window, three strategies were employed. For ten of the strongest psoriasis signals, we used a whole-region approach which included non-coding intergenic and intronic sequence. For four established loci of lesser significance, we targeted all full transcription units within the +/- 250 kb interval. For the remaining signals, we targeted the exons of all transcription units within the +/- 250 kb interval. Due to complexities of high-efficiency targeting of HLA genes we selected 5 specific candidate genes for sequencing near the HLA-C gene. </p>
| phs000766 | dbGaP
Project description:Genome-wide DNA methylation profiling of motile spermatozoa from 23 patients with psoriasis without arthritis, 13 psoriatic arthritis, and 18 unaffected controls using the Infinium HumanMethylation 450k v1 platform.
2019-02-02 | GSE126017 | GEO
Project description:The efficacy of monoclonal antibodies against either interleukin (IL)-17 or the IL-17 receptor in psoriasis therapy provides strong evidence that IL-17 is the major inflammatory mediation in this disease. However, how IL-17 induces epidermal hyperplasia in psoriasis remains largely unknown. Here, we show that IL-17 actives NF-kB in keratinocytes and initiates the NF-kB-dependent transcription of microRNA-31 (miR-31), one of the most abundant microRNAs in the epidermis of lesional skin of psoriasis and two related mouse models. Similar to IL-17 deficiency (IL-17-/-), knocking out miR-31 (miR-31-/-) or targeting it by antagomir-31 prevents keratinocytes Ki67 expression and inhibits acanthosis and dermal inflammation in psoriasis mouse model. Moreover, PPP6c, a negative regulator restricting G0/G1 to G2/M phase progression in the cell cycle, is diminished in human psoriatic epidermis and is directly targeted by miR-31. Inhibition of ppp6c is functionally important for the biological effects of miR-31 in the development of epidermal hyperplasia. Thus, our data define IL-17-inducede miR-31 and its target ppp6c as critical factors for hyperproliferative epidermis in psoriasis. Epidermis samples from affected ears derived from 3 CD18hypo PL/J mice (DIS) or normal ears derived from 3 CD18hypo C57BL/6J mice(2128) were used for RNA extraction and hybridization on Affymetrix microarrays. We sought to compare miRNA expression of normal skin from control and lesional skin.
2013-12-31 | E-GEOD-50099 | biostudies-arrayexpress