Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia

Background: Fetal immune tolerance is crucial for pregnancy success. We studied the link between preeclampsia, a severe pregnancy disorder with uncertain pathogenesis, and fetal human leukocyte antigen G (HLA-G) and other genes regulating maternal immune responses.Methods: We assessed sex ratios and regulatory HLA-G haplotypes in population cohorts and series of preeclampsia and stillbirth. We studied placental mRNA expression of 136 genes by sequencing and HLA-G and interferon alpha (IFN alpha) protein expression by immunohistochemistry.Findings: We found underrepresentation of males in preeclamptic births, especially those delivered preterm or small for gestational age. Balancing selection at HLA-G associated with the sex ratio, stillbirth, and preeclampsia. We observed downregulation of HLA-G, its receptors, and many other tolerogenic genes, and marked upregulation of IFNA1 in preeclamptic placentas.Interpretation: These findings indicate that an evolutionary trade-off between immune tolerance and protection against infections at the maternal-fetal interface promotes genetic diversity in fetal HLA-G, thereby affecting survival, preeclampsia, and sex ratio. We highlight IFNA1 as a potential mediator of preeclampsia and a target for therapeutic trials. (C) 2020 The Authors. Published by Elsevier B.V.</div

Discovery of Molecular Markers to Discriminate Corneal Endothelial Cells in the Human Body

The corneal endothelium is a monolayer of hexagonal corneal endothelial cells (CECs) on the inner surface of the cornea. CECs are critical in maintaining corneal transparency through their barrier and pump functions. CECs in vivo have a limited capacity in proliferation, and loss of a significant number of CECs results in corneal edema called bullous keratopathy which can lead to severe visual loss. Corneal transplantation is the most effective method to treat corneal endothelial dysfunction, where it suffers from donor shortage. Therefore, regeneration of CECs from other cell types attracts increasing interests, and specific markers of CECs are crucial to identify actual CECs. However, the currently used markers are far from satisfactory because of their non-specific expression in other cell types. Here, we explored molecular markers to discriminate CECs from other cell types in the human body by integrating the published RNA-seq data of CECs and the FANTOM5 atlas representing diverse range of cell types based on expression patterns. We identified five genes, CLRN1, MRGPRX3, HTR1D, GRIP1 and ZP4 as novel markers of CECs, and the specificities of these genes were successfully confirmed by independent experiments at both the RNA and protein levels. Notably none of them have been documented in the context of CEC function. These markers could be useful for the purification of actual CECs, and also available for the evaluation of the products derived from other cell types. Our results demonstrate an effective approach to identify molecular markers for CECs and open the door for the regeneration of CECs in vitro

Viral infection-related gene upregulation in monocytes in children with signs of β-cell autoimmunity

Abstract Objective: The pathogenesis of type 1 diabetes (T1D) is associated with genetic predisposition and immunological changes during presymptomatic disease. Differencesin immune cell subset numbers and phenotypes between T1D patients and healthy controls have been described; however, the role and function of these changes in the pathogenesis is still unclear. Here we aimed to analyze the transcriptomic landscapes of peripheral blood mononuclear cells (PBMCs) during presymptomatic disease. Methods: Transcriptomic differences in PBMCs were compared between cases positive for islet autoantibodies and autoantibody negative controls (9 case–control pairs)and further in monocytes and lymphocytes separately in autoantibody positive subjects and control subjects (25 case–control pairs). Results: No significant differential expression was found in either data set. However, when gene set enrichment analysis was performed, the gene sets “defence response to virus” (FDR &lt;0.001, ranking 2), “response to virus” (FDR &lt;0.001, ranking 3) and “response to type I interferon” (FDR=0.002, ranking 12) were enriched in the upregulated genes among PBMCs in cases. Upon further analysis, this was also seen in monocytes in cases (FDR=0.01, ranking 2; FDR=0.04, ranking 3 and FDR=0.02, ranking 1, respectively) but not in lymphocytes. Conclusion: Gene set enrichment analysis of children with T1D-associated autoimmunity revealed changes in pathways relevant for virus infection in PBMCs, particularly in monocytes. Virus infections have been repeatedly implicated in the pathogenesis of T1D. These results support the viral hypothesis by suggesting altered immune activation of viral immune pathways in monocytes during diabetes

The International Linear Collider: Report to Snowmass 2021

The International Linear Collider (ILC) is on the table now as a new global energy-frontier accelerator laboratory taking data in the 2030s. The ILC addresses key questions for our current understanding of particle physics. It is based on a proven accelerator technology. Its experiments will challenge the Standard Model of particle physics and will provide a new window to look beyond it. This document brings the story of the ILC up to date, emphasizing its strong physics motivation, its readiness for construction, and the opportunity it presents to the US and the global particle physics community