Interferon-alpha mediates the development of autoimmunity by direct tissue toxicity and through immune-cell recruitment mechanisms
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA134511 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR094744.fastq.gz | Fastqsanger.gz | |||
| SRR094745.fastq.gz | Fastqsanger.gz | |||
| SRR094746.fastq.gz | Fastqsanger.gz | |||
| SRR094747.fastq.gz | Fastqsanger.gz | |||
| SRR094748.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 5 |
Similar Datasets
Project description:Interferon-alpha is a major therapeutic agent for many diverse diseases. However, the interferon-alpha mechanism of therapeutic action and associated side effects are not well understood. In particular, thyroiditis is a common unexplained complication. We hypothesized that direct thyroid-toxic actions coupled with immune mechanisms play a major role in the thyroiditis etiology. To test this hypothesis, we investigated the actions of interferon-alpha on cultured thyrocytes in vitro, and in vivo by creating transgenic mice overexpressing interferon-alpha tissue specifically in thyrocytes. Interferon-alpha treatment of cultured PCCL3 rat thyrocytes increased markers of thyroid differentiation, levels of MHC class I, and expression of heat shock protein and CXCL10. This was associated with markedly increased nonapoptotic thyroid cell death. Consistent with these in vitro findings, transgenic mice overexpressing interferon-alpha in the thyroid displayed striking thyroid cell death characteristic of nonimmune thyroid destruction that progressed to profound primary hypothyroidism. Moreover, genes linked to cell death pathways, granzyme B, or known to be associated with recruitment of a cytotoxic immune response, CXCL10, interleukin-23, and TRIM21 were increased in the transgenic thyroids. Taken together, the etiology of interferon-induced thyroiditis likely involves both a direct toxic action on thyrocytes, as well as provocation of a destructive immune response. 1) Thyroid cells were incubated with interferon-alpha, and global gene expression was determined by RNA-seq. 2) Thyroid tissues were obtained from transgenic mice overexpressing interferon-alpha and from wild type mice, and global gene expression was analyzed using RNA-seq.
2011-11-03 | E-GEOD-25115 | biostudies-arrayexpress
Project description:Interferon-alpha is a major therapeutic agent for many diverse diseases. However, the interferon-alpha mechanism of therapeutic action and associated side effects are not well understood. In particular, thyroiditis is a common unexplained complication. We hypothesized that direct thyroid-toxic actions coupled with immune mechanisms play a major role in the thyroiditis etiology. To test this hypothesis, we investigated the actions of interferon-alpha on cultured thyrocytes in vitro, and in vivo by creating transgenic mice overexpressing interferon-alpha tissue specifically in thyrocytes. Interferon-alpha treatment of cultured PCCL3 rat thyrocytes increased markers of thyroid differentiation, levels of MHC class I, and expression of heat shock protein and CXCL10. This was associated with markedly increased nonapoptotic thyroid cell death. Consistent with these in vitro findings, transgenic mice overexpressing interferon-alpha in the thyroid displayed striking thyroid cell death characteristic of nonimmune thyroid destruction that progressed to profound primary hypothyroidism. Moreover, genes linked to cell death pathways, granzyme B, or known to be associated with recruitment of a cytotoxic immune response, CXCL10, interleukin-23, and TRIM21 were increased in the transgenic thyroids. Taken together, the etiology of interferon-induced thyroiditis likely involves both a direct toxic action on thyrocytes, as well as provocation of a destructive immune response.
2011-11-03 | GSE25115 | GEO
Project description:IFN-? is known to play a key role in autoimmunity, but the mechanisms are uncertain. Although the induction of autoimmunity by IFN-? is consistent with primarily immunomodulatory effects, the high frequency of nonautoimmune inflammation suggests other mechanisms. We used thyroiditis as a model to dissect these possibilities. IFN-? treatment of cultured thyrocytes increased expression of thyroid differentiation markers, thyroglobulin, thyroid-stimulating hormone receptor, thyroid peroxidase, and sodium iodide transporter. RNAseq analysis demonstrated that pathways of Ag presentation, pattern recognition receptors, and cytokines/chemokines were also stimulated. These changes were associated with markedly increased nonapoptotic thyroid cell death, suggesting direct toxicity. To corroborate these in vitro findings, we created transgenic mice with thyroid-specific overexpression of IFN-? under control of the thyroglobulin promoter. Transgenic mice developed marked inflammatory thyroid destruction associated with immune cell infiltration of thyroid and surrounding tissues leading to profound hypothyroidism, findings consistent with our in vitro results. In addition, transgenic mice thyroids showed upregulation of pathways similar to those observed in cultured thyrocytes. In particular, expression of granzyme B, CXCL10, a subset of the tripartite motif-containing family, and other genes involved in recruitment of bystander cytotoxic immune responses were increased. Pathways associated with apoptosis and autophagy were not induced. Taken together, our data demonstrate that the induction of tissue inflammation and autoimmunity by IFN-? involves direct tissue toxic effects as well as provocation of destructive bystander immune responses.
| S-EPMC3106338 | biostudies-literature
Project description:The gastrointestinal ecosystem is a highly complex environment with a profound influence on human health. Inflammation in the gut, linked to an altered gut microbiome has been associated with the development of multiple human conditions including type 1 diabetes (T1D). Viruses infecting the gastrointestinal tract, especially enteroviruses, are also thought to play an important role in T1D pathogenesis possibly via overlapping mechanisms. Here, we apply an integrative approach to combine comprehensive faecal virome, microbiome and metaproteome data sampled before and at the onset of islet autoimmunity in 40 children. We show strong age and antibody related effects across the datasets. Mastadenovirus infection was associated with profound functional changes in the faecal metaproteome. Multiomic factor analysis modelling revealed proteins associated with carbohydrate transport from the genus Faecalibacterium were associated with islet autoimmunity. These findings demonstrate functional remodelling of the gut microbiota accompanies both islet autoimmunity and viral infection.
2022-08-22 | PXD032997 | Pride
Project description:This study demonstrates quantitative and qualitative differences between type I IFN signatures in autoimmunity and viral infection using purified CD4pos T cells and CD16pos- and CD16neg-monocyte subsets. We were able to discriminate between cell-specific viral response signatures and the pathogenically amplified IFN signatures observed in autoimmunity. The differences were of both a qualitative and quantitative nature, as the signatures in the patients with SLE were characterized by much more complexly compiled gene patterns with increased absolute gene expression levels.
2014-01-06 | GSE51997 | GEO
Project description:Natural killer (NK) cells provide in vivo control of orthopoxvirus infections in association with their expansion in the draining lymph node (LN), where they are normally very rare. The mechanism of this expansion is unclear. Herein, we determined that NK-cell depletion results in enhanced infection following footpad inoculation of cowpox virus, a natural pathogen of rodents. Following cowpox virus infection in normal mice, NK cells were greatly expanded in the draining LN, were not replicating, and displayed markers similar to splenic NK cells, suggesting specific recruitment of splenic NK cells rather than in situ proliferation. Moreover, NK-cell expansion was abrogated by prior injection of clodronate-loaded liposomes, indicating a role for subcapsular sinus macrophages. Furthermore, recruitment of transferred splenic NK cells to the draining LN was pertussis toxin-sensitive, suggesting involvement of chemokine receptors. Comprehensive analysis of chemokine mRNA expression in the draining LN following infection suggested the selective involvement of CCR2, CCR5, and/or CXCR3. Mice deficient for CCR2 or CCR5 had normal NK-cell recruitment, whereas CXCR3-deficient mice displayed a major defect, which was NK cell-intrinsic. Interestingly, both induction of transcripts for CXCR3 ligands (Cxcl9 and Cxcl10) and NK-cell recruitment required IFN-?. These data indicate that NK-cell recruitment is mediated by subcapsular sinus macrophages, IFN-?, and CXCR3 during orthopoxvirus infection.
| S-EPMC3538256 | biostudies-literature
Project description:Apoptotic cell (AC) clearance is essential for immune homeostasis. Here we show that mouse CD300f (CLM-1) recognizes outer membrane-exposed phosphatidylserine, and regulates the phagocytosis of ACs. CD300f accumulates in phagocytic cups at AC contact sites. Phosphorylation within CD300f cytoplasmic tail tyrosine-based motifs initiates signals that positively or negatively regulate AC phagocytosis. Y276 phosphorylation is necessary for enhanced CD300f-mediated phagocytosis through the recruitment of the p85? regulatory subunit of phosphatidylinositol-3-kinase (PI3K). CD300f-PI3K association leads to activation of downstream Rac/Cdc42 GTPase and mediates changes of F-actin that drive AC engulfment. Importantly, primary macrophages from CD300f-deficient mice have impaired phagocytosis of ACs. The biological consequence of CD300f deficiency is predisposition to autoimmune disease development, as Fc?RIIB-deficient mice develop a systemic lupus erythematosus-like disease at a markedly accelerated rate if CD300f is absent. In this report we identify the mechanism and role of CD300f in AC phagocytosis and maintenance of immune homeostasis.
| S-EPMC4151829 | biostudies-literature