Project description:Autoimmune diseases, such as rheumatoid arthritis, are associated with significant gut microbiota dysbiosis. Here we show that remodelling of 24h rhythms within the gut during inflammatory joint disease drives profound changes in the microbiome and gut permeability.
Project description:Single-cell analysis of the transcriptome, T cell immune receptors, and surface proteome (CITE-seq) from peripheral blood mononuclear cells (PBMCs) of COVID-19 patients with pre-existing autoimmune diseases (rheumatoid arthritis n = 5, psoriasis n = 4, or multiple sclerosis n = 3), as well as COVID-19 patients without pre-existing autoimmunity as controls (n = 10) to investigate altered immune responses.
Project description:Lymph node stromal cells (LNSCs) are an important lymphoid tissue cellular type that regulates the immune response and maintain peripheral tolerance. In rheumatoid arthritis, break of tolerance and formation of autoantibodies occurs years before arthritis. Studies in mice have shown lymph nodes activation before the onset of arthritis. We hypothesize that malfunctioning of LNSCs leads to a microenvironment where immune responses are not properly controlled leading to activation of (autoreactive) lymphocytes and the production of autoantibodies. Here we studied human LNSCs and search for differentially methylated genes between RA versus healthy using Illumina human methylation arrays in order to identify new epigenetic targets.
Project description:Lymph node stromal cells (LNSCs) are an important lymphoid tissue cellular type that regulates the immune response and maintain peripheral tolerance. In rheumatoid arthritis, break of tolerance and formation of autoantibodies occurs years before arthritis. Studies in mice have shown lymph nodes activation before the onset of arthritis. We hypothesize that malfunctioning of LNSCs leads to a microenvironment where immune responses are not properly controlled leading to activation of (autoreactive) lymphocytes and the production of autoantibodies. Here we studied human LNSCs and search for differentially expressed genes between RA at risk or RA versus healthy using RNA sequencing in order to identify new therapeutic targets.
Project description:Altered tryptophan catabolism has been identified in inflammatory diseases like rheumatoid arthritis (RA) and spondyloarthritis (SpA), but the causal mechanisms linking tryptophan metabolites to disease are unknown. Using the collagen-induced arthritis (CIA) model we identify alterations in tryptophan metabolism, and specifically indole, that correlate with disease. We demonstrate that both bacteria and dietary tryptophan are required for disease, and indole supplementation is sufficient to induce disease in their absence. When mice with CIA on a low-tryptophan diet were supplemented with indole, we observed significant increases in serum IL-6, TNF, and IL-1β; splenic RORγt+CD4+ T cells and ex vivo collagen-stimulated IL-17 production; and a pattern of anti-collagen antibody isotype switching and glycosylation that corresponded with increased complement fixation. IL-23 neutralization reduced disease severity in indole-induced CIA. Finally, exposure of human colon lymphocytes to indole increased expression of genes involved in IL-17 signaling and plasma cell activation. Altogether, we propose a mechanism by which intestinal dysbiosis during inflammatory arthritis results in altered tryptophan catabolism, leading to indole stimulation of arthritis development. Blockade of indole generation may present a novel therapeutic pathway for RA and SpA.
Project description:To characterize the progenitor-enriched CD44+NGFR+ cells present in the crypt and surface regions of the tonsil, we used an Illumina array system to analyze the transcriptome of these cells isolated from the tonsillar crypt and surface regions of three different individuals as well as the total epithelial (CD45-CD31-) populations obtained from two of these. To enrich for epithelial progeniors in human palatine tonsil tissue, hematopoietic and endothelial cells were depleted from freshly isolated cell suspensions derived from palatine tonsils using fluorescence-activated cell sorting (FACS). The resultant CD45-CD31- population was further fractionated into four subpopulations using antibodies against CD44 and NGFR. Based on the immunohistochemical phenotype and in vitro functional assays, CD44+NGFR+ subpopulations were identified as epithelial progenitor-enriched subsets. Microarray profiling was used to derive gene expression signatures of CD45-CD31- subsets (total epithelial-enriched) and CD45-CD31-CD44+NGFR+ subpopulations (progenitor-enriched).
