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Genetically-driven target tissue over-expression of CD40: A novel mechanism in autoimmune disease

ABSTRACT: Genetically-driven target tissue over-expression of CD40: A novel mechanism in autoimmune disease

PROVIDER: PRJNA169916 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR517615.fastq.gz	Fastqsanger.gz
	SRR517616.fastq.gz	Fastqsanger.gz
	SRR517617.fastq.gz	Fastqsanger.gz
	SRR517618.fastq.gz	Fastqsanger.gz
	SRR517619.fastq.gz	Fastqsanger.gz

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Genetically-driven target tissue over-expression of CD40: A novel mechanism in autoimmune disease

Project description:The CD40 gene, an important immune regulatory gene, is also expressed and functional on non-myeloid derived cells, many of which are targets for tissue specific autoimmune diseases, including d thyroid follicular cells in Graves’ disease (GD). Whether target tissue CD40 expression plays a role in autoimmune disease etiology has yet to be determined. Here we show for the first time, that target-tissue over-expression of CD40 plays a key role in the etiology of autoimmunity. Using a murine model of GD, we demonstrated that thyroidal CD40 over-expression augmented the production of thyroid specific antibodies, resulting in more severe experimental autoimmune Graves’ disease (EAGD), whereas deletion of thyroidal CD40 suppressed disease. Using transcriptome and immune-pathway analyses we showed that in both EAGD mouse thyroids and human primary thyrocytes, CD40 mediates this effect by activating downstream cytokines and chemokines, most notably IL-6. To translate these findings into therapy, we blocked IL-6 during EAGD induction in the setting of thyroidal CD40 over-expression, and showed decreased levels of TSHR stimulating antibodies and frequency of disease. We conclude that target tissue over-expression of CD40 plays a key role in the etiology of organ specific autoimmune disease. CD40 in Thyroid Autoimmunity: 1) Incubation of human thyroid cells with G28.5, a CD40 stimulating antibody, and purification of RNA, conversion to cDNA, measurement of mRNA expression using RNAseq. 2) Removal of thyroid tissues from CD40 over-expressing transgenic mice and wild type mice, purification of RNA, conversion to cDNA measurement of mRNA expression using RNAseq.

2012-10-03 | E-GEOD-39081 | biostudies-arrayexpress

Genetically-driven target tissue over-expression of CD40: A novel mechanism in autoimmune disease

2012-10-03 | GSE39081 | GEO

Genetically driven target tissue overexpression of CD40: a novel mechanism in autoimmune disease.

Project description: Not available

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CD40-activation of human B cells

Project description:Antibody-independent effector functions of B cells, such as antigen presentation and cytokine production, have been shown to play an important role in a variety of immune-mediated conditions such as autoimmune diseases, transplant rejection and graft-versus-host disease. Therapeutic strategies, which interfere with B cell activation could therefore be a useful addition to the current immunosuppressive armamentarium. CD40 is one of the strongest activation stimuli for B cells. The aim of this study was to characterise the gene expression changes that occurr after B cell activation via CD40. Purified B cells isolated from PBMCs from four donors were compared to B cells which

2014-01-14 | E-GEOD-54017 | biostudies-arrayexpress

CD40-activation of human B cells

2014-01-14 | GSE54017 | GEO

Quantitative proteomics confirms CpKRS is over-expressed in genetically modified strain.

Project description:C. parvum was genetically modified to over-express CpKRS. The CpTK locus was replaced wit a cassette containing CpKRS and the dual reporter-selection marker, Nluc-NeoR, driven by the CpEnolase promoter. Quantitative proteomics analysis confirms over-expression of CpKRS and similar significantly increased expression of Nluc-NeoR.

2024-07-05 | PXD050089 | Pride

Integrin β3 Deficiency Unleashes Spontaneous Pulmonary Inflammation by Promoting B Cell Hyperactivation via the CD40-CD40L Axis

Project description:Background: Pulmonary immune homeostasis relies on stringent control of adaptive immunity. Integrin β3 is a critical mediator of cellular adhesion and platelet function. However, its specific role in modulating adaptive immunity, particularly B cell immune response, remains poorly understood.Results: We identified that β3⁻/⁻ mice showed a spontaneous pulmonary inflammation characterized by B cell activation and in situ immune complex deposition in alveoli. Multi-omics integration identified that the CD40-CD40 Ligand (CD40L) axis was strongly implicated in this pathology process. Mechanistically, the absence of β3 potentiates CD40L-CD40 engagement on B cells, leading to hyperactivation of the NF-κB pathway. Notably, reduced ITGB3 expression in patients with autoimmune disease correlated significantly with enhanced transcriptional signatures of B cell activation and inflammation.Methods: Histopathology characterized the pulmonary phenotype of constitutive β3-deficient (β3⁻/⁻) mice. Integrated transcriptomic and proteomic profiling of lung tissue was then performed to map the molecular landscape of spontaneous pulmonary inflammation. Related mechanisms were investigated by histopathology and functional assays, and established clinical relevance by analyzing transcriptomic datasets from patients with autoimmune diseases.Conclusions: Our findings redefine integrin β3 as a threshold regulator of the B cell activation. Consequently, the β3-CD40L-CD40 axis represents a promising therapeutic target for managing B cell-related autoimmune diseases.

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Proteome profiling of GC1-spg cells over-expressing Autoimmune Regulator (AIRE)

Project description:This project was aimed at evaluating the influence of Autoimmune Regulator in gene expression in GC1-spg cells.

2016-06-14 | PXD002511 | Pride