| 1. |
- Gallardo-Dodd, Carlos J., et al.
(författare)
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Exposure of volunteers to microgravity by dry immersion bed over 21 days results in gene expression changes and adaptation of T cells
- 2023
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Ingår i: Science Advances. - 2375-2548. ; 9:34
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Tidskriftsartikel (refereegranskat)abstract
- The next steps of deep space exploration are manned missions to Moon and Mars. For safe space missions for crew members, it is important to understand the impact of space flight on the immune system. We studied the effects of 21 days dry immersion (DI) exposure on the transcriptomes of T cells isolated from blood samples of eight healthy volunteers. Samples were collected 7 days before DI, at day 7, 14, and 21 during DI, and 7 days after DI. RNA sequencing of CD3(+) T cells revealed transcriptional alterations across all time points, with most changes occurring 14 days after DI exposure. At day 21, T cells showed evidence of adaptation with a transcriptional profile resembling that of 7 days before DI. At 7 days after DI, T cells again changed their transcriptional profile. These data suggest that T cells adapt by rewiring their transcriptomes in response to simulated weightlessness and that remodeling cues persist when reexposed to normal gravity.
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| 2. |
- Seitz, Christina
(författare)
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Lineage stability and effector function of CD4+FOXP3+ regulatory T cells
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This work focuses on regulatory T (Treg) cell biology in the context of defining the role of forkhead box protein 3 (FOXP3) isoform expression and Treg mediated suppression via CTLA-4 (cytotoxic T-lymphocyte-associated protein 4). Treg cells are crucial in maintaining immunological tolerance and they in part act by suppressing dendritic cells (DCs). Previous studies have demonstrated that Treg cells express the co-inhibitory receptor CTLA-4, which is essential for Treg cells ability to control the expression of the costimulatory molecules CD80/CD86 on DCs. In study I we generated a novel mouse strain that exclusively expresses the naturally occurring ligand-independent CTLA-4 isoform (liCTLA-4) in Treg cells only. This isoform cannot control CD80/CD86 expression by direct binding to these molecules. One of the key findings in this study is that these Ctla4ex2fl/flFoxp3-Cre mice did not develop a lymphoproliferative phenotype early in life. When we extended our study, we saw that older Ctla4ex2fl/flFoxp3-Cre mice (6 months) developed an inflammatory phenotype in the lung. Interestingly, Ctla4ex2fl/flFoxp3-Cre mice had an increased number of Treg cells, in particular Treg cells lacking CD25 expression. The dramatic increase of Treg cells could potentially compensate for any functional impairment due to altered CTLA-4 expression. Thus, we isolated Treg cells for in vitro assays to further investigate Treg cell function using an DC suppression assay that we established. We found that Treg cells isolated from Ctla4ex2fl/flFoxp3-Cre were able to control CD80 and CD86 expression. However, Treg cells isolated from Ctla4ex2fl/flFoxp3-Cre failed to support upregulation of PD-L2 on suppressed DCs. The transcription factor FOXP3 is a key regulator for Treg cell differentiation and is required to maintain their suppressive phenotype. FOXP3 occurs as four distinct isoforms, full-length FOXP3 and isoforms lacking exon 2 and or exon 7. In study II we determined the FOXP3 isoform expression in plaques and blood from patients suffering from atherosclerotic disease. We found a positive correlation between FOXP3D2 splice variant expression and plaque stability in plaque tissue that was not apparent in blood. Another key finding from this study is that during Treg cell activation the overall upregulation of FOXP3 expression is mainly due to an increased expression of the isoform FOXP3D2. In study III and IV we reported on two patients with a novel frameshift mutation in the FOXP3 gene (NM_014009.3:c.305delT) located in exon 2 which results in a premature stop codon and consequently the loss of any isoforms expressing exon 2. Both patients had a very mild IPEX phenotype, which strongly suggests FOXP3D2 alone is able to at least partially maintain Treg cell development and function. Investigating the female carrier, we saw approximately 20% of the Treg pool had the c.305delT mutation not matching the expected 50% from random X-chromosome inactivation. RNA sequencing allowed us to identify a set of genes, several which previously have been demonstrated to regulate FOPX3 expression, that are specifically regulated by fulllength FOXP3. This gene set may explain the loss of c.305delT Treg cells and we currently favor the view that they regulate the lineage stability of Treg cells.
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| 3. |
- Walton, Esther, et al.
(författare)
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Brain Structure in Acutely Underweight and Partially Weight-Restored Individuals With Anorexia Nervosa : A Coordinated Analysis by the ENIGMA Eating Disorders Working Group
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 92:9, s. 730-738
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The pattern of structural brain abnormalities in anorexia nervosa (AN) is still not well understood. While several studies report substantial deficits in gray matter volume and cortical thickness in acutely underweight patients, others find no differences, or even increases in patients compared with healthy control subjects. Recent weight regain before scanning may explain some of this heterogeneity. To clarify the extent, magnitude, and de-pendencies of gray matter changes in AN, we conducted a prospective, coordinated meta-analysis of multicenter neuroimaging data.METHODS: We analyzed T1-weighted structural magnetic resonance imaging scans assessed with standardized methods from 685 female patients with AN and 963 female healthy control subjects across 22 sites worldwide. In addition to a case-control comparison, we conducted a 3-group analysis comparing healthy control subjects with acutely underweight AN patients (n = 466) and partially weight-restored patients in treatment (n = 251).RESULTS: In AN, reductions in cortical thickness, subcortical volumes, and, to a lesser extent, cortical surface area were sizable (Cohen's d up to 0.95), widespread, and colocalized with hub regions. Highlighting the effects of un-dernutrition, these deficits were associated with lower body mass index in the AN sample and were less pronounced in partially weight-restored patients.CONCLUSIONS: The effect sizes observed for cortical thickness deficits in acute AN are the largest of any psychiatric disorder investigated in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium to date. These results confirm the importance of considering weight loss and renutrition in biomedical research on AN and underscore the importance of treatment engagement to prevent potentially long-lasting structural brain changes in this population.
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