Fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Katerina Akassoglou
PROVIDER: E-GEOD-71084 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:This SuperSeries is composed of the following subset Series: GSE18023: Mice with FIA develop anti-native and anti-in vitro citrullinated fibrinogen antibodies GSE18024: FIA plasma induces arthritis in naïve mice GSE18025: Fibrinogen-reactive T cells transfer disease to naïve mice Refer to individual Series
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Project description:Synovial antigen arrays were probed with 1:150 dilutions of plasma derived from SJL mice immunized with fibrinogen emulsified in CFA or with CFA alone. Autoantibody binding was detected with a Cy3-conjugated goat-anti-mouse IgG/M secondary antibody. SAM was applied to identify antigens with statistically significant differences in array reactivity between FIA and CFA control plasma (q < 0.01) obtained from mice before boosting. The SAM hits were subjected to hierarchical cluster analysis and are displayed as a heatmap. Synovial array profiling of FIA plasma demonstrated autoreactive B-cell responses against peptides representing native fibrinogen, and B-cell epitope spreading resulting in additional targeting of citrullinated fibrinogen in the samples obtained before boosting. Custom-spotted protein slides were probed with plasma samples from individual mice. Four slides were probed with plasma derived from mice immunized with CFA and six slides were probed with plasma derived from mice immunized with fibrinogen emulsified in CFA.
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Project description:Splenocytes harvested from mice with FIA were cultured in vitro and stimulated with 0.01 mg/ml fibrinogen for 3 days. Enriched T cells were transferred into 6-week-old naïve SJL mice, which developed visible signs of arthritis within 2 weeks. Synovial array profiling of plasma from the arthritic recipient mice demonstrated autoreactive B cell responses against peptides representing native fibrinogen, and further spreading of the responses to target collagen type V, cartilage gp39, and citrullinated vimentin. Custom-spotted protein slides were with plasma samples from individual mice. Four slides were probed with plasma derived from naïve mice and five slides were probed with plasma derived from mice injected with FIA T cells.
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Project description:Collagen- and fibrin-based gels are extensively used to study cell behaviour. However, 2D-3D, collagen-fibrin, and in vivo-in vitro comparisons of gene expression, cell shape and mechanotransduction have not been reported. Here we compared chick tendon fibroblasts (CTFs) at three stages of embryonic development with CTFs cultured in collagen- or fibrin-based tissue engineered constructs (TECs).
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Project description:Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Although it has been extensively studied, the proximate trigger of the immune response remains uncertain. Experimental autoimmune encephalomyelitis in the common marmoset recapitulates many radiological and pathological features of focal multiple sclerosis lesions in the cerebral white matter, unlike traditional experimental autoimmune encephalomyelitis in rodents. This provides an opportunity to investigate how lesions form as well as the relative timing of factors involved in lesion pathogenesis, especially during early stages of the disease. We used MRI to track experimental autoimmune encephalomyelitis lesions in vivo to determine their age, stage of development, and location, and we assessed the corresponding histopathology post-mortem. We focused on the plasma protein fibrinogen-a marker for blood-brain barrier leakage that has also been linked to a pathogenic role in inflammatory demyelinating lesion development. We show that fibrinogen has a specific spatiotemporal deposition pattern, apparently deriving from the central vein in early experimental autoimmune encephalomyelitis lesions <6 weeks old, and preceding both demyelination and visible gadolinium enhancement on MRI. Thus, fibrinogen leakage is one of the earliest detectable events in lesion pathogenesis. In slightly older lesions, fibrinogen is found inside microglia/macrophages, suggesting rapid phagocytosis. Quantification demonstrates positive correlation of fibrinogen deposition with accumulation of inflammatory cells, including microglia/macrophages and T cells. The peak of fibrinogen deposition coincides with the onset of demyelination and axonal loss. In samples from chronic multiple sclerosis cases, fibrinogen was found at the edge of chronic active lesions, which have ongoing demyelination and inflammation, but not in inactive lesions, suggesting that fibrinogen may play a role in sustained inflammation even in the chronic setting. In summary, our data support the notion that fibrinogen is a key player in the early pathogenesis, as well as sustained inflammation, of inflammatory demyelinating lesions.
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Project description:This SuperSeries is composed of the SubSeries listed below.
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Project description:Disulfide bonds link pairs of cysteine amino acids and their formation is assumed to be complete in the mature, functional protein. We tested this assumption by quantifying the redox state of disulfide bonds in the thrombosis protein, fibrinogen. There is an extraordinary disulfide lability in fibrinogen, with 13 bonds in the protein ranging from 10 to 50% reduced in human donors, indicating that fibrinogen exists in hundreds of different disulfide-bonded states. The significance of this finding for fibrinogen conversion to fibrin was investigated. Fibrin polymer formation triggers formation of disulfides in fibrin molecules, which is required for a robust fibrin matrix that withstands the mechanical forces of flowing blood and resists premature fibrinolysis. The covalent states of fibrinogen are changed by fluid shear forces ex vivo and in vivo, indicating that the different states are dynamic. These findings demonstrate that proteins can exist and function as a multitude of covalent forms.
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