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- Ishigaki, Kazuyoshi, et al.
(author)
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Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis
- 2022
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In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:11, s. 1640-1651
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Journal article (peer-reviewed)abstract
- Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 × 10−8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.
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- Schmidt, Peter, et al.
(author)
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A new murine model of islet xenograft rejection : Graft destruction is dependent on a major histocompatibility-specific interaction between T-cells and macrophages
- 2003
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 52:5, s. 1111-1118
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Journal article (peer-reviewed)abstract
- A new murine model of porcine islet-like cell cluster (ICC) xenograft rejection, avoiding interference of unspecific inflammation, was introduced and used to investigate rejection mechanisms. Athymic (nu/nu) mice were transplanted with syngeneic, allogeneic, or xenogeneic islets under the kidney capsule. After the original transplantation, immune cells in porcine ICC xenografts undergoing rejection in native immunocompetent mice were transferred to the peritoneal cavity of the athymic mice. At defined time points after transfer, the primary grafts were evaluated by immunohistochemistry and real-time quantitative RT-PCR to estimate cytokine and chemokine mRNA expression. Transfer of immunocompetent cells enabled athymic (nu/nu) mice to reject a previously tolerated ICC xenograft only when donor and recipient were matched for major histocompatibility complex (MHC). In contrast, allogeneic and syngeneic islets were not rejected. The ICC xenograft rejection was mediated by transferred T-cells. The main effector cells, macrophages, were shown to be part of a specific immune response. By day 4 after transplantation, there was an upreglation of both Th1- and Th2-associated cytokine transcripts. The transferred T-cells were xenospecific and required MHC compatibility to induce rejection. Interaction between the TCR of transferred T-cells and MHC on host endothelial cells and/or macrophages seems necessary for inducing ICC xenograft rejection.
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- Van Maldeghem, Flore, et al.
(author)
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Chrome-rich spinels in micrometeorites from modern Antarctic sedimentary deposits
- 2024
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In: Earth and Planetary Science Letters. - 0012-821X. ; 641
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Journal article (peer-reviewed)abstract
- Each year, approximately 5000 tons of extraterrestrial material reaches the Earth's surface as micrometeorites, cosmic dust particles ranging from 10 to 2000 μm in size. These micrometeorites, collected from diverse environments, mainly deep-sea sediments, Antarctic ice, snow and loose sediments, and hot deserts, are crucial in understanding our Solar System's evolution. Chrome-rich spinel (Cr-spinel) minerals have gained attention as proxies for studying the extraterrestrial flux in sedimentary deposits, because these robust minerals occur, in various extraterrestrial materials, with compositions characteristic of their parent bodies. A total of 27 Cr-spinel bearing micrometeorites within the size range of 185–800 μm, were identified from approximately 6000 micrometeorites from the Transantarctic Mountains (n = 23) and the Sør Rondane Mountains (n = 4), in Antarctica, containing Cr-spinel (8–120 μm), were examined in this study for geochemical composition and high-precision oxygen isotope ratios to assess alteration and identify potential parent bodies. Oxygen isotopes in the micrometeorite groundmass and in Cr-spinel grains reveal a predominance of ordinary chondritic precursors, with only 1 in 10 micrometeorites containing Cr-spinel minerals showing a carbonaceous chondritic signature. This may be further confirmed by an elevated Al content (> 12 wt% Al2O3) in Cr-spinel from specific carbonaceous chondrite types, but a more extensive dataset is required to establish definitive criteria. The first Cr-spinel bearing particle, in an Antarctic micrometeorite, that can be linked to R-chondrites based on oxygen isotopes, has been documented, demonstrating the potential for R-chondrites as a source of chrome-rich spinels. The study also highlights the potential for chemical modifications and alteration processes that Cr-spinel minerals may undergo during their time on the parent body, atmospheric entry, and terrestrial residence. In the context of the broader micrometeorite flux, the results align with previous findings, showing a consistent contribution of micrometeorites containing Cr-spinel minerals related to ordinary chondrites over the past 2 to 4 million years. This is however a small fraction (∼ 1 %) of the total micrometeorite flux. The study further confirms that Cr-spinel minerals recovered from sedimentary deposits serve as valuable proxies for tracking events related to ordinary chondritic or achondritic materials. However, it is emphasized that Cr-spinel minerals alone cannot serve as exclusive indicators of the overall extraterrestrial flux, especially during periods dominated by carbonaceous chondritic dust in the inner Solar System. To comprehensively understand the complete extraterrestrial flux, additional proxies are needed to trace dust-producing events associated with various Solar System objects. The intricate nature of Cr-spinel compositions, and the potential for alteration processes emphasize the need for further research to refine our understanding of these extraterrestrial markers.
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