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Preeclampsia (PE) generally manifests in the second half of pregnancy with hypertension and proteinuria. The understanding of the origin and mechanism behind PE is incomplete, although there is clearly an immune component to this disorder. The placenta constitutes a complicated immune interface between fetal and maternal cells, where regulation and tolerance are key. Stress factors from placental dysfunction in PE are released to the maternal circulation evoking the maternal response. Several complement factors play a role within this intricate landscape, including C1q in vascular remodeling and Factor H (FH) as the key regulator of alternative pathway complement activation. We hypothesize that decreased levels of C1q or FH, or disturbance of their function by autoantibodies, may be associated with PE. Autoantibodies against C1q and FH and the concentrations of C1q and FH were measured by ELISA in maternal sera from women with preeclamptic and normal pregnancies. Samples originated from cohorts collected in the Netherlands (n=63 PE; n=174 control pregnancies, n=51 nonpregnant), Finland (n=181 PE; n=63 control pregnancies) and Norway (n=59 PE; n=27 control pregnancies). Serum C1q and FH concentrations were higher in control pregnancy than in nonpregnant women. No significant differences were observed for serum C1q between preeclamptic and control pregnancy in any of the three cohorts. Serum levels of FH were lower in preeclamptic pregnancies compared to control pregnancies in two of the cohorts, this effect was driven by the early onset PE cases. Neither anti-C1q autoantibodies nor anti-FH autoantibodies levels differed between women with PE and normal pregnancies. In conclusion, levels of anti-C1q and anti-FH autoantibodies are not increased in PE. C1q and FH are increased in pregnancy, but importantly, a decrease in FH concentration is associated with PE. publishedVersion

The Asian “tiger mosquito” Aedes albopictus is currently the most widely distributed disease-transmitting mosquito in the world. Its geographical expansion has also allowed the expansion of multiple arboviruses like dengue, Zika, and chikungunya, to higher latitudes. Due to the enormous risk to global public health caused by mosquitoes species vectors of human disease, and the challenges in slowing their expansion, it is necessary to develop new and environmentally friendly vector control strategies. Among these, host-associated microbiome-based strategies have emerged as promising options. In this study, we performed an RNA-seq analysis on dissected abdomens of Ae. albopictus females from Manhattan, KS, United States fed with sugar and human blood containing either normal or heat-inactivated serum, to evaluate the effect of heat inactivation on gene expression, the bacteriome transcripts and the RNA virome of this mosquito species. Our results showed at least 600 genes with modified expression profile when mosquitoes were fed with normal vs. heat-inactivated-containing blood. These genes were mainly involved in immunity, oxidative stress, lipid metabolism, and oogenesis. Also, we observed bacteriome changes with an increase in transcripts of Actinobacteria, Rhodospirillaceae, and Anaplasmataceae at 6 h post-feeding. We also found that feeding with normal blood seems to particularly influence Wolbachia metabolism, demonstrated by a significant increase in transcripts of this bacteria in mosquitoes fed with blood containing normal serum. However, no differences were observed in the virome core of this mosquito population. These results suggest that heat and further inactivation of complement proteins in human serum may have profound effect on mosquito and microbiome metabolism, which could influence interpretation of the pathogen-host interaction findings when using this type of reagents specially when measuring the effect of Wolbachia in vector competence.

Purpose Advanced age-related macular degeneration (AAMD) risk is associated with rare complement Factor I (FI) genetic variants associated with low FI protein levels (termed ‘Type 1’), but it is unclear how variant prevalences differ between AMD patients from different ethnicities. Methods Collective prevalence of Type 1 CFI rare variant genotypes were examined in four European AAMD datasets. Collective minor allele frequencies (MAFs) were sourced from the natural history study SCOPE, the UK Biobank, the International AMD Genomics Consortium (IAMDGC), and the Finnish Biobank Cooperative (FINBB), and compared to paired control MAFs or background population prevalence rates from the Genome Aggregation Database (gnomAD). Due to a lack of available genetic data in non-European AAMD, power calculations were undertaken to estimate the AAMD population sizes required to identify statistically significant association between Type 1 CFI rare variants and disease risk in different ethnicities, using gnomAD populations as controls. Results Type 1 CFI rare variants were enriched in all European AAMD cohorts, with odds ratios (ORs) ranging between 3.1 and 7.8, and a greater enrichment was observed in dry AMD from FINBB (OR 8.9, 95% CI 1.49–53.31). The lack of available non-European AAMD datasets prevented us exploring this relationship more globally, however a statistical association may be detectable by future sequencing studies that sample approximately 2,000 AAMD individuals from Ashkenazi Jewish and Latino/Admixed American ethnicities. Conclusions The relationship between Type 1 CFI rare variants increasing odds of AAMD are well established in Europeans, however the lack of broader genetic data in AAMD has adverse implications for clinical development and future commercialisation strategies of targeted FI therapies in AAMD. These findings emphasise the importance of generating more diverse genetic data in AAMD to improve equity of access to new treatments and address the bias in health care.

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OBJECTIVE: Cortical grey matter (GM) pathology, involving demyelination and neurodegeneration, associated with meningeal inflammation, could be important in determining disability progression in multiple sclerosis (MS). However, we need to know more about how cortical demyelination, neurodegeneration and meningeal inflammation contribute to pathology in early stages of MS to better predict long-term outcome.METHODS: Tissue blocks from short disease duration MS (n=12, median disease duration 2 years), progressive MS (n=21, disease duration 25 years), non-diseased controls (n=11) and other neurological inflammatory disease controls (n=6), were quantitatively analysed by immunohistochemistry, immunofluorescence and in situ hybridisation.RESULTS: Cortical GM demyelination was extensive in some cases of acute MS (range 1- 48% of total cortical GM) and subpial lesions were the most common type (62%). The numbers of activated (CD68+) microglia/ macrophages were increased in cases with subpial lesions and the density of neurons was significantly reduced in acute MS normal appearing and lesion GM, compared to controls (pINTERPRETATION: Our findings demonstrate that cortical demyelination, neuronal loss and meningeal inflammation are notable pathological hallmarks of acute MS and support the need to identify early biomarkers of this pathology to better predict outcome. This article is protected by copyright. All rights reserved.

Ischaemia and reperfusion injury (IRI) is the leading cause of acute kidney injury (AKI), which contributes to high morbidity and mortality rates in a wide range of injuries as well as the development of chronic kidney disease. The cellular and molecular responses of the kidney to IRI are complex and not fully understood. Here, we used an integrated proteomic and metabolomic approach to investigate the effects of IRI on protein abundance and metabolite levels. Rat kidneys were subjected to 45 min of warm ischaemia followed by 4 h and 24 h reperfusion, with contralateral and separate healthy kidneys serving as controls. Kidney tissue proteomics after IRI revealed elevated proteins belonging to the acute phase response, coagulation and complement pathways, and fatty acid (FA) signalling. Metabolic changes were already evident after 4 h reperfusion and showed increased level of glycolysis, lipids and FAs, whilst mitochondrial function and ATP production was impaired after 24 h. This deficit was partially compensated for by the contralateral kidney. Such a metabolic balance counteracts for the developing energy deficit due to reduced mitochondrial function in the injured kidney.

Although in the last few years in general the biocompatibility of biomaterials has significantly improved, unwanted tissue reactions are often observed resulting in early resorption of the biomaterial, loosening of the implant or in a chronic (immunologic) response. From immunologic studies it is known that inflammatory reactions can be modulated by use of (anti) growth factors or anti-inflammatory drugs. Before this can be employed the role of individual factors (humoral and cellular) involved in the inflammatory reaction against biomaterials has to be studied. In this part of the study the role of macrophages is studied with and without depletion by use of the liposomes-mediated macrophage suicide technique. Crosslinked dermal sheep collagens were used as biodegradable test materials. The results showed that macrophage depletion increases vascularization, and decreases the infiltration of granulocytess into the collagens. The foreign body reaction, i.e. the infiltration of macrophages and giant cells was significantly inhibited, resulting in a strongly delayed degradation time of the biomaterials. However, macrophage depletion did not inhibit attraction of fibroblasts and even resulted in increased formation of autologous rat-collagen, which improved the biocompatibility and the function of the biomaterials as a tempory scaffold.

Although in the last few years in general the biocompatibility of biomaterials has significantly improved, unwanted tissue reactions are often observed resulting in early resorption of the biomaterial, loosening of the implant or in a chronic (immunologic) response. From immunologic studies it is known that inflammatory reactions can be modulated by use of (anti) growth factors or anti-inflammatory drugs. Before this can be employed the role of individual factors (humoral and cellular) involved in the inflammatory reaction against biomaterials has to be studied. In this part of the study the role of macrophages is studied with and without depletion by use of the liposomes-mediated macrophage suicide technique. Crosslinked dermal sheep collagens were used as biodegradable test materials. The results showed that macrophage depletion increases vascularization, and decreases the infiltration of granulocytess into the collagens. The foreign body reaction, i.e. the infiltration of macrophages and giant cells was significantly inhibited, resulting in a strongly delayed degradation time of the biomaterials. However, macrophage depletion did not inhibit attraction of fibroblasts and even resulted in increased formation of autologous rat-collagen, which improved the biocompatibility and the function of the biomaterials as a tempory scaffold.

Although in the last few years in general the biocompatibility of biomaterials has significantly improved, unwanted tissue reactions are often observed resulting in early resorption of the biomaterial, loosening of the implant or in a chronic (immunologic) response. From immunologic studies it is known that inflammatory reactions can be modulated by use of (anti) growth factors or anti-inflammatory drugs. Before this can be employed the role of individual factors (humoral and cellular) involved in the inflammatory reaction against biomaterials has to be studied. In this part of the study the role of macrophages is studied with and without depletion by use of the liposomes-mediated macrophage suicide technique. Crosslinked dermal sheep collagens were used as biodegradable test materials. The results showed that macrophage depletion increases vascularization, and decreases the infiltration of granulocytess into the collagens. The foreign body reaction, i.e. the infiltration of macrophages and giant cells was significantly inhibited, resulting in a strongly delayed degradation time of the biomaterials. However, macrophage depletion did not inhibit attraction of fibroblasts and even resulted in increased formation of autologous rat-collagen, which improved the biocompatibility and the function of the biomaterials as a tempory scaffold.