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Systemic lupus erythematosus (SLE) is a heterogeneous multifactorial disease. Upregulated TLR7 signaling is a known risk factor for SLE. Recently, it was shown that specific genetic variants in UNC93B1 affect the physiological regulation of TLR7 signaling and cause characteristic autoimmune phenotypes with monogenic autosomal recessive inheritance in mutant mice and dogs. We therefore hypothesized that homologous variants in the human UNC93B1 gene might be responsible for a fraction of human SLE patients. We analyzed 536 patients of the Swiss SLE Cohort Study for the presence of genetic variants affecting the C-terminal tail of UNC93B1. None of the investigated patients carried bi-allelic UNC93B1 variants that were likely to explain their SLE phenotypes. We conclude that genetic variants affecting the C-terminal tail of UNC93B1 are not a common risk factor for SLE. It cannot be excluded that such variants might contribute to other heritable autoimmune diseases.

Additional file 8: Supplementary Figures. Fig. S1. Characterization of regulated mRNAs. (A) Sample clustering based on the expression of the 84 top regulated mRNAs (p value1 and mean of read counts>50 read). (B) Scree plot for visualization of the percentage of variances explained for each principle component (eigenvalues) in RNA sequencing data (C) Contingency table of the 18 top regulated mRNAs displaying the (multivariate) frequency distribution of the variables. The diameter of the orange circle for each gene per patient provides an estimate of the probability for that particular gene to represent that particular patient. (D) Volcano plot of all mRNAs using adjusted P value. Fig. S2. Characterization of regulated miRNAs. (A) Sample clustering based on the expression of the 18 top regulated miRNAs (p-value1 and mean of read counts>50 read) (B) Scree plot for visualization of the variances in miRNA sequencing data (C) Contingency table of the 8 top regulated miRNAs displaying the (multivariate) frequency distribution of the variables. The diameter of the orange circle for each miRNA per patient provides an estimate of the probability for that particular miRNA to represent that particular patient. (D) Volcano plot of all miRNAs using adjusted P value. Fig. S3. Validation of regulated miRNAs by NanoString. Radar graph visualizing the average log2 fold change of 16 miRNAs significantly regulated in NanoString or sequencing dataset (p-value1 and mean of read counts>300 read). The red line represents the NGS miRNA sequencing data and purple line represents the NanoString data. Red area is showing the upregulation and green area is representing downregulation.

BACKGROUND & AIMS Paneth cells (PCs) synthesize and secrete antimicrobial peptides that are key mediators of host-microbe interactions, establishing a balance between intestinal microflora and enteric pathogens. We observed that their number increases in experimental portal hypertension and aimed to investigate the mechanisms by which these cells can contribute to the regulation of portal pressure. METHODS We first treated Math1Lox/LoxVilcreERT2 mice with tamoxifen to induce the complete depletion of intestinal PCs. Subsequently, we performed partial portal vein or bile duct ligation. We then studied the effects of these interventions on hemodynamic parameters, proliferation of blood vessels and the expression of genes regulating angiogenesis. Intestinal organoids were cultured and exposed to different microbial products to study the composition of their secreted products (by proteomics) and their effects on the proliferation and tube formation of endothelial cells (ECs). In vivo confocal laser endomicroscopy was used to confirm the findings on blood vessel proliferation. RESULTS Portal hypertension was significantly attenuated in PC-depleted mice compared to control mice and was associated with a decrease in portosystemic shunts. Depletion of PCs also resulted in a significantly decreased density of blood vessels in the intestinal wall and mesentery. Furthermore, we observed reduced expression of intestinal genes regulating angiogenesis in Paneth cell depleted mice using arrays and next generation sequencing. Tube formation and wound healing responses were significantly decreased in ECs treated with conditioned media from PC-depleted intestinal organoids exposed to intestinal microbiota-derived products. Proteomic analysis of conditioned media in the presence of PCs revealed an increase in factors regulating angiogenesis and additional metabolic processes. In vivo endomicroscopy showed decreased vascular proliferation in the absence of PCs. CONCLUSIONS These results suggest that in response to intestinal flora and microbiota-derived factors, PCs secrete not only antimicrobial peptides, but also pro-angiogenic signaling molecules, thereby promoting intestinal and mesenteric angiogenesis and regulating portal hypertension. LAY SUMMARY Paneth cells are present in the lining of the small intestine. They prevent the passage of bacteria from the intestine into the blood circulation by secreting substances to fight bacteria. In this paper, we discovered that these substances not only act against bacteria, but also increase the quantity of blood vessels in the intestine and blood pressure in the portal vein. This is important, because high blood pressure in the portal vein may result in several complications which could be targeted with novel approaches.

Failed or altered gliogenesis is a major characteristic of diffuse white matter injury in survivors of premature birth. The developmentally regulated long noncoding RNA (lncRNA) H19 inhibits S-adenosylhomocysteine hydrolase (SAHH) and contributes to methylation of diverse cellular components, such as DNA, RNA, proteins, lipids, and neurotransmitters. We showed that the pregnancy-derived synthetic PreImplantation Factor (sPIF) induces expression of the nuclear receptor corepressor 2 (NCOR2) via H19/SAHH-mediated DNA demethylation. In turn, NCOR2 affects oligodendrocyte differentiation markers. Accordingly, after hypoxic-ischemic brain injury in rodents, myelin protection and oligodendrocytes' fate are in part modulated by sPIF and H19. Our results revealed an unexpected mechanism of the H19/SAHH axis underlying myelin preservation during brain recovery and its use in treating neurodegenerative diseases can be envisioned.